C5-anilinoquinazoline compounds and their use in treating cancer

ABSTRACT

The invention concerns compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3  and R 4  have any of the meanings hereinbefore defined in the description; process for their preparation; pharmaceutical compositions containing them and their use in treating KIT mediated diseases.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Patent Application No. 62/490,859, filed on Apr. 27, 2017,the entirety of which is hereby incorporated by reference.

FIELD OF INVENTION

The specification generally relates to C₅-anilinoquinazoline compoundsand pharmaceutically acceptable salts thereof. These compounds and theirpharmaceutically acceptable salts selectively modulate KIT, includingwildtype KIT and primary and secondary KIT mutations, and thespecification therefore also relates to the use of such compounds andsalts thereof to treat or prevent KIT mediated disease, includingcancer. The specification further relates to crystalline forms ofC₅-anilinoquinazoline compounds and pharmaceutically acceptable saltsthereof; pharmaceutical compositions comprising such compounds andsalts; kits comprising such compounds and salts; methods of manufactureof such compounds and salts; and to methods of treating KIT mediateddisease, including cancer, using such compounds and salts.

BACKGROUND

Receptor tyrosine kinases (RTK) can be oncogenic drivers in cancer dueto genetic aberrations such as amplification, mutations or fusion eventsor via overexpression (M. A. Lemmon, K. M. Ferguson, Cell 130, 213(2007)). Most aberrations in RTK result in ligand-independent activationof the receptor and activation of downstream signalling promoting cellgrowth and proliferation and increased survival. The class III RTKincluding KIT, platelet-derived growth factor receptor (PDGFR) alpha andbeta, colony-stimulating factor 1 receptor (CSF1R), and the Fms-liketyrosine kinase 3 receptor (FLT3) is implicated in a variety of humancancers (K. Verstraete. S. N. Savvides, Nat. Rev. Cancer 12, 753(2012)).

The gene encoding KIT is located on Chr 4 and comprises 21 exons (J.Lennartsson, L. Ronnstrand, Physiol Rev. 92, 1619 (2012)). The 976 aminoacids of the KIT protein are divided into key domains: an extracellulardomain, a transmembrane domain, a juxtamembrane domain (JM) and kinasedomain separated by a kinase insert (KID) in the middle. The matureprotein is ˜145 KDa following N glycosylation and is expressed at thecell surface. Following stem cell factor (SCF) binding, the dimerisationincreases the intrinsic kinase activity phosphorylating tyrosineresidues in the JM domain (Y547, Y553, Y568 and Y570) followed byphosphorylations in the KID (Y703, Y721, Y729/730) and finally theactivation loop (Y823) (J. P. DiNitto et al., J. Biochem. 147, 601(2010)). Some phosphoylations sites on KIT are key docking sites foradaptors and downstream effectors propagating the activation signal.PI3K, Src and MAPK are key signalling pathways activated downstream ofKIT. Regulation of KIT signalling includes internalization andsubsequent degradation of the receptor, phosphorylation of Ser 741 and746, and dephosphorylation of tyrosine residues by phosphatases such asSHP1.

KIT-driven signaling plays a key role in specific cell types, includinginterstitial cells of Cajal (ICCs), melanocytes, mast cells, germ cellsand some hematopoietic stem cells (J. Lennartsson, L. Ronnstrand,Physiol Rev. 92, 1619 (2012)). Aberrations of KIT are observed inmalignancies derived from these cell types. For example, KIT mutationsare reported in gastrointestinal stromal tumours (originating from ICC),in mastocytosis and in melanomas.

Mutations in KIT in cancer affect multiple exons with hotspot mutationsobserved in the JM and kinase domains (J. Lennartsson, L. Ronnstrand,Physiol Rev. 92, 1619 (2012)). Mutations in the JM domain are thought toremove the autoinhibitory interaction of the JM domain with the kinasedomain (J. P. DiNitto et al., J. Biochem. 147, 601 (2010)). Lowerfrequency mutations are present in exon 9 (extracellular Ig domain 5)and 13 (ATP binding pocket and gatekeeper). Mutations in the JM domainare observed in GIST while mutations affecting the kinase domain, inparticular the A loop are frequently observed in mastocytosis.Similarly, PDGFR mutations in GIST affect both the JM domain and thekinase domain (C. Bahlawane et al., Cell Commun. Signal. 13, 21 (2015)).

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymaltumors of the gastrointestinal tract (C. M. Barnett, C. L. Corless, M.C. Heinrich. Hematol. Oncol. Clin. North Am. 27, 871 (2013)). GISTs aremost commonly found in the stomach and small intestine. Neoplastic GISToriginate from the same precursor cells as the ICC and the vast majorityof GIST express KIT protein initially called CD117. KIT mutationsaffecting exon 11 were first identified in GIST in 1998 (S. Hirota etal., Science 279, 577 (1998)). The same publication also reported theoncogenicity of KIT mutations expressed ectopically in Ba/F3 cells andtheir constitutive kinase activation. 75-80% GIST harbor KIT mutationsand ˜10% PDGFR mutations (J. A. Fletcher, Cancer Res. 76, 6140 (2016)).Rare aberrations in BRAF, NF1 and SDH account for what is referred to asWT KIT (C. M. Barnett, C. L. Corless, M. C. Heinrich, Hematol. Oncol.Clin. North Am. 27, 871 (2013)).

Imatinib was the first KIT inhibitor tested in GIST, demonstratingremarkable activity in patients with advanced GIST (G. D. Demetri etal., N. Engl. J. Med. 347, 472 (2002), J. Verweij et al., Lancet 364,1127 (2004), C. D. Blanke et al., J. Clin. Oncol. 26, 626 (2008)). Ameta-analysis of 2 large clinical studies concluded that patients withexon 9 mutations in KIT or other mutations had worse prognosis thanpatients with exon 11 mutations (Metagist, J. Clin. Oncol. 28, 1247(2010)). In addition, a high dose imatinib (800 mg) did not improveprogression-free survival in patients with exon 9 mutations compared tothe standard dose (400 mg). Clinical resistance to imatinib was firstreported in 2005 (C. R. Antonescu et al., Clin. Cancer Res. 11, 4182(2005)) but a larger study following patients treated with imatinib aspart of a PhII study B2222 showed a reactivation of KIT and KITsignalling with patients who have initially benefited from imatinibrelapsed (M. C. Heinrich et al., J. Clin. Oncol. 24, 4764 (2006)).Secondary resistance mutations were noted at key residues: V654A in theATP-binding pocket, T670I at the gatekeeper residue and A loop (D816X,D820X, N822K, Y823D). In addition, so called “primary resistance” toimatinib was mainly observed in patients with exon9 mutations. Overall,50% of patients developed resistance within 2 years (C. D. Blanke etal., J. Clin. Oncol. 26, 626 (2008).).

Sunitinib is a multikinase inhibitor including KIT and PDGFR. Sunitinibdemonstrated clinical activity in GIST patients following progression onimatinib (G. D. Demetri et al., Lancet 368, 1329 (2006)). Clinicalbenefit with sunitinib was observed in patients with primary exon 9mutations. In addition, patients with secondary mutations affecting exon13 and 14 had longer progression-free and overall survival compared topatients with secondary mutations affecting the A loop (M. C. Heinrichet al., J. Clin. Oncol. 26, 5352 (2008)). Clinical progression withsunitnib was observed within 1 year of treatment. Ectopic expression ofKIT with primary and secondary mutations in CHO cells showed thatsunitinib reduced KIT phosphorylation preferentially when KITaberrations affected the ATP binding pocket or the gatekeeper.

Regorafenib, another multikinase inhibitor has shown clinical activityin patients with GIST after relapse to imatinib and sunitinib (G. D.Demetri et al., Lancet 381, 295 (2013)). The PhIII study reported amedian PFS of 4.8 months.

Accordingly, there is a need for KIT inhibitors that inhibit secondaryKIT mutations, and furthermore, are selective against KDR, particularlyas existing treatments are ineffective against such secondary mutations.There is also a need for KIT inhibitors that inhibit primary KITmutations and wildtype KIT.

SUMMARY

The compounds of the disclosure have been found to possess potentanti-tumour activity, being useful in inhibiting a range of secondaryKIT mutations, including V654A, D816H and T670I, as well as primarymutations and wildtype KIT, and furthermore are selective against KDR.The compounds of the disclosure have the required pharmaceuticalproperties, for example, good PK properties.

Briefly, this specification describes, in part, a compound of Formula(I):

or a pharmaceutically acceptable salt thereof, wherein:—R¹ is selected from hydrogen and fluoro;R² is selected from fluoro and C₁₋₂ alkoxy;R³ is selected from hydrogen and methoxy; andR⁴ is a C₁₋₃ alkyl, optionally substituted with a group selected fromC₁₋₃ alkoxy and NR⁵R⁶, where R⁵ and R⁶ are each independently hydrogenor methyl; or a 4 to 6 membered heterocyclyl ring containing one oxygenatom.

This specification also describes, in part, a pharmaceutical compositionwhich comprises a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablediluent or carrier.

This specification also describes, in part, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for use in therapy.

This specification also describes, in part, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for use in the treatmentof cancer.

This specification also describes, in part, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of cancer.

This specification also describes, in part, a method for treating cancerin a warm blooded animal in need of such treatment, which comprisesadministering to the warm-blooded animal a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof.

BRIEF DESCRIPTION OF THE FIGURES

Figure A shows the XRPD for Form A ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide(Compound X, Example 12).

Figure B shows the DSC for Form A ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide(Compound X, Example 12).

Figure C shows the XRPD for Form B ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide(Compound X, Example 12).

Figure D shows the DSC for Form B ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide(Compound X, Example 12).

Figure E shows the XRPD for Form A ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidetosylate salt (Tosylate Salt Y, Example 12A).

Figure F shows the DSC for Form A ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidetosylate salt (Tosylate Salt Y, Example 12A).

Figure G shows the XRPD for Form B ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidetosylate salt (Toslate Salt Y, Example 12A).

Figure H shows the DSC for Form B ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidetosylate salt (Tosylate Salt Y. Example 12A).

Figure I shows the XRPD for Form D of N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidetosylate salt (Tosylate Salt Y, Example 12A).

Figure J shows the DSC for Form D ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidetosylate salt (Toslate Salt Y, Example 12A).

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Many embodiments of the invention are detailed throughout thespecification and will be apparent to a reader skilled in the art. Theinvention is not to be interpreted as being limited to any particularembodiment(s) thereof.

In the first embodiment there is provided a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:—R¹ is selected from hydrogen and fluoro;R² is selected from fluoro and C₁₋₂ alkoxy;R³ is selected from hydrogen or methoxy; andR⁴ is a C₁₋₃ alkyl, optionally substituted with a group selected fromC₁₋₃ alkoxy and NR⁵R⁶, where R⁵ and R⁶ are each independently hydrogenor methyl; or a 4 to 6 membered heterocyclyl ring containing one oxygenatom.

Suitable 4 to 6 membered heterocyclyl rings containing one oxygen atominclude an oxetanyl ring, a tetrahydrofuranyl ring and an oxanyl ring.

The term “oxetanyl” ring includes oxetan-3-yl, the structure of which isshown below:

The term “tetrahydrofuranyl” includes tetrahydrofuran-3-yl, thestructure of which is shown below:

The term “oxanyl” ring includes oxan-3-yl and oxan-4-yl groups, thestructures of which are shown below:

In the above structures the dashed line indicates the bonding positionof the relevant group.

An oxanyl ring may also be referred to as a tetrahydropyranyl ring.Similarly, an oxan-4-yl ring may be referred to as atetrahydropyran-4-yl ring, and an oxan-3-yl ring may be referred to as atetrahydropyran-3-yl ring.

The prefix C_(p-q) in C_(p-q) alkyl and other terms (where p and q areintegers) indicates the range of carbon atoms that are present in thegroup, for example C₁₋₃ alkyl includes C₁ alkyl (methyl), C₂ alkyl(ethyl) and C₃ alkyl (propyl as n-propyl and isopropyl).

The term C_(p-q) alkoxy comprises —O—C_(p-q) alkyl groups.

Where the term “optionally” is used, it is intended that the subsequentfeature may or may not occur. As such, use of the term “optionally”includes instances where the feature is present, and also instanceswhere the feature is not present. For example, a group “optionallysubstituted by one methoxy group” includes groups with and without amethoxy substituent.

The term “substituted” means that one or more hydrogens (for example oneor two hydrogens, or alternatively one hydrogen) on the designated groupis replaced by the indicated substituent(s) (for example one or twosubstituents, or alternatively one substituent), provided that anyatom(s) bearing a substituent maintains a permitted valency. Substituentcombinations encompass only stable compounds and stable syntheticintermediates. “Stable” means that the relevant compound or intermediateis sufficiently robust to be isolated and have utility either as asynthetic intermediate or as an agent having potential therapeuticutility. If a group is not described as “substituted”, or “optionallysubstituted”, it is to be regarded as unsubstituted (i.e. that none ofthe hydrogens on the designated group have been replaced).

The term “pharmaceutically acceptable” is used to specify that an object(for example a salt, dosage form, diluent or carrier) is suitable foruse in patients. An example list of pharmaceutically acceptable saltscan be found in the Handbook of Pharmaceutical Salts: Properties,Selection and Use, P. H. Stahl and C. G. Wermuth, editors,Weinheim/Zürich:Wiley-VCH/VHCA, 2002. A suitable pharmaceuticallyacceptable salt of a compound of Formula (I) is, for example, an acidaddition salt. An acid addition salt of a compound of Formula (I) may beformed by bringing the compound into contact with a suitable inorganicor organic acid under conditions known to the skilled person. An acidaddition salt may for example be formed using an inorganic acid selectedfrom the group consisting of hydrochloric acid, hydrobromic acid,sulphuric acid and phosphoric acid. An acid addition salt may also beformed using an organic acid selected from the group consisting oftrifluoroacetic acid, citric acid, maleic acid, oxalic acid, aceticacid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaricacid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonicacid and para-toluenesulfonic acid.

In one embodiment, there is provided a compound of Formula (I) or apharmaceutically acceptable salt thereof, where the pharmaceuticallyacceptable salt is a tosylate, mesylate or besylate salt. These saltsshowed improved handling properties for formulations comprisingcompounds of Formula (I). In one embodiment, there is provided acompound of Formula (I) or a pharmaceutically acceptable salt thereof,where the pharmaceutically acceptable salt is a tosylate salt. In oneembodiment, there is provided a compound of Formula (I) or apharmaceutically acceptable salt thereof, where the pharmaceuticallyacceptable salt is a mono-tosylate salt, i.e. the stoichiometry of thecompound of the Formula (I) to tosylate is 1:1.

A further embodiment provides any of the embodiments defined herein (forexample the embodiment of claim 1) with the proviso that one or morespecific Examples (for instance, one, two or three specific Examples)selected from the group consisting of Examples 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 12A, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22 isindividually disclaimed.

A further embodiment provides any of the embodiments defined herein (forexample the embodiment of claim 1) with the proviso that one or morespecific Examples (for instance, one, two or three specific Examples)selected from the group consisting of Examples 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22 is individuallydisclaimed.

In one embodiment, R¹ is hydrogen. In one embodiment, R¹ is fluoro.

In one embodiment, R² is selected from fluoro, methoxy and ethoxy. Inone embodiment, R² is fluoro. In one embodiment, R² is methoxy. In oneembodiment, R² is ethoxy.

In one embodiment, R³ is hydrogen. In one embodiment, R³ is methoxy.

In one embodiment, R⁴ is selected from C₁₋₃ alkyl optionally substitutedwith a group selected from methoxy and NR⁵R⁶ where R⁵ and R⁶ are eachindependently hydrogen or methyl; and an oxetanyl, a tetrahydrofuranyland an oxanyl ring.

In one embodiment, R⁴ is selected from C₁₋₃ alkyl optionally substitutedwith a group selected from methoxy and NR⁵R⁶ where R⁵ and R⁶ are eachmethyl; and an oxetanyl, a tetrahydrofuranyl and an oxanyl ring.

In one embodiment, R⁴ is selected from methyl, ethyl, isopropyl,2-(dimethylamino)ethyl, 2-methoxyethyl, oxetan-3-yl,tetrahydrofuran-3-yl and oxan-4-yl.

In one embodiment, R⁴ is methyl. In one embodiment, R⁴ is ethyl. In oneembodiment, R⁴ is isopropyl.

In one embodiment, R⁴ is 2-dimethylaminoethyl. In one embodiment, R⁴ is2-methoxyethyl. In one embodiment, R⁴ is oxetan-3-yl. In one embodiment,R⁴ is tetrahydrofuran-3-yl. In one embodiment, R⁴ is oxan-4-yl.

In one embodiment, R¹ is hydrogen, R² is methoxy, R³ is hydrogen and R⁴is methyl.

In one embodiment, R¹ is hydrogen, R² is fluoro, R³ is hydrogen and R⁴is 2-methoxyethyl.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of:

-   N-{4-[(5,7-dimethoxyquinazolin-4-yl)amino]-3-fluorophenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;-   N-{4-[(5-fluoro-6,7-dimethoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;-   (R)—N-(4-{[5-Ethoxy-7-(tetrahydrofuran-3-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;-   (S)—N-(4-{[5-Ethoxy-7-(tetrahydrofuran-3-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;-   N-(4-((5-Ethoxy-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide;-   N-(4-((7-(2-(Dimethylamino)ethoxy)-5-ethoxyquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide;-   N-(4-((5-Ethoxy-7-methoxyquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide;-   N-(4-((5-Ethoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide;-   N-(4-((5-Ethoxy-7-(oxetan-3-yloxy)quinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide;-   N-(4-{[5-Methoxy-7-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;-   2-[4-(Propan-2-yl)-1H-1,2,3-triazol-1-yl]-N-{4-[(5,6,7-trimethoxyquinazolin-4-yl)amino]phenyl}acetamide;-   N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;-   (R)-2-(4-Isopropyl-1H-1,2,3-triazol-1-yl)-N-(4-((5-methoxy-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)phenyl)acetamide;-   (S)-2-(4-Isopropyl-1H-1,2,3-triazol-1-yl)-N-(4-((5-methoxy-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)phenyl)acetamide;-   N-(4-{[5-Methoxy-7-(propan-2-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;-   N-(4-{[5-Methoxy-7-(oxetan-3-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;-   N-[4-({7-[2-(Dimethylamino)ethoxy]-5-methoxyquinazolin-4-yl}amino)phenyl]-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;-   N-{4-[(7-Ethoxy-5-methoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;-   N-{4-[(5,7-Diethoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;-   N-(4-{[5-Methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;-   N-{4-[(5-Fluoro-7-methoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;    and-   N-{4-[(5,7-Dimethoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of:

-   N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;    and-   N-{4-[(5,7-Dimethoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the compound isN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide.

In one embodiment there is provided a compound of Formula (I) whereinthe compound isN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide,in the free base form (also referred to as Compound X).

In one embodiment there is provided a compound of Formula (I) whereinthe compound is N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidetosylate salt (also referred to as Tosylate Salt Y).

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the compound isN-{4-[(5,7-Dimethoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide.

Compounds and salts described in this specification may exist insolvated forms and unsolvated forms. For example, a solvated form may bea hydrated form, such as a hemi-hydrate, a mono-hydrate, a di-hydrate, atri-hydrate or an alternative quantity thereof. The inventionencompasses all such solvated and unsolvated forms of compounds ofFormula (I), particularly to the extent that such forms possess KITinhibitory activity, as for example measured using the tests describedherein.

Atoms of the compounds and salts described in this specification mayexist as their isotopes. The invention encompasses all compounds ofFormula (I) where an atom is replaced by one or more of its isotopes(for example a compound of Formula (I) where one or more carbon atom isan ¹¹C or ¹³C carbon isotope, or where one or more hydrogen atoms is a²H or ³H isotope, or where one or more nitrogen atoms is a ¹⁵N isotopeor where one of more oxygen atoms is an ¹⁷O or ¹⁸O isotope).

Compounds and salts described in this specification may exist inoptically active or racemic forms by virtue of one or more asymmetriccarbon atoms. The invention includes any optically active or racemicform of a compound of Formula (I) which possesses KIT inhibitoryactivity, as for example measured using the tests described herein. Thesynthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis using optically active materials or by resolution of a racemicform.

Therefore, in one embodiment there is provided a compound of Formula(I), or a pharmaceutically acceptable salt thereof, which is a singleoptical isomer being in an enantiomeric excess (% e.e.) of ≥95%, ≥98% or≥99%. In one embodiment, the single optical isomer is present in anenantiomeric excess (% e.e.) of ≥99%.

Some of the compounds of Formula (I) may be crystalline and may havemore than one crystalline form. It is to be understood that theinvention encompasses any crystalline or amorphous form, or mixturesthereof, which possess properties useful in KIT inhibitory activity. Itis well known how to determine the efficacy of a crystalline oramorphous form by the standard tests described hereinafter.

It is generally known that crystalline materials may be analysed usingconventional techniques such as, for example, X-ray powder diffraction(hereinafter XRPD) analysis and Differential Scanning Calorimetry(hereinafter DSC).

As an example, the compound of Example 12. Compound X, exhibitscrystallinity and two crystalline forms, Form A and Form B, have beenidentified and have been obtained using the conditions describedhereinafter in the experimental section.

Polymorphic Form A of Compound X

Accordingly, a further aspect of the invention is Form A of Compound X(Example 12).

According to the invention there is provided a crystalline form, Form A,of Compound X which has an XRPD pattern with at least one specific peakat about 2-theta=6.7°, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form A,of Compound X which has an XRPD pattern with at least one specific peakat about 2-theta=18.7°, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form A.of Compound X which has an XRPD pattern with at least two specific peaksat about 2-theta=6.7° and 18.7°, measured by CuKα radiation.

According to the invention there is provided a crystalline form, Form A,of Compound X which has an XRPD pattern with specific peaks at about2-theta=3.4, 6.7, 9.9, 16.2, 18.7, 22.1, 23.3 25.1, 26.6, 28.9°,measured using CuKα radiation.

According to the invention there is provided crystalline form, Form A.of Compound X which has an XRPD pattern substantially the same as theXRPD pattern shown in Figure A, measured using CuKα radiation.

According to the invention there is provided crystalline form, Form A,of Compound X which has an XRPD pattern with at least one specific peakat 2-theta=6.7° plus or minus 0.2° 2-theta, measured using CuKαradiation.

According to the invention there is provided a crystalline form, Form A,of Compound X which has an XRPD pattern with at least one specific peakat 2-theta=18.7° plus or minus 0.2° 2-theta, measured using CuKαradiation.

According to the invention there is provided a crystalline form, Form A,of Compound X which has an XRPD pattern with at least two specific peaksat 2-theta=6.7° and 18.7° wherein said values may be plus or minus 0.2°2-theta, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form A,of Compound X which has an XRPD pattern with specific peaks at2-theta=3.4, 6.7, 9.9, 16.2, 18.7, 22.1, 23.3 25.1, 26.6, 28.9° whereinsaid values may be plus or minus 0.2° 2-theta, measured using CuKαradiation.

DSC analysis of Compound X. Form A shows a melting endotherm with anonset of 235.7° C. and a peak at 237.6° C. (Figure B).

Thus DSC analysis shows Compound X, Form A is a high melting solid withan onset of melting at about 235.7° C. and a peak at about 237.6° C.

Polymorphic Form B of Compound X

A further aspect of the invention is Form B of Compound X.

According to the invention there is provided a crystalline form, Form B,of Compound X which has an XRPD pattern with at least one specific peakat about 2-theta=4.2°, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form B,of Compound X which has an XRPD pattern with at least one specific peakat about 2-theta=7.7°, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form B,of Compound X which has an XRPD pattern with at least two specific peaksat about 2-theta=4.2° and 7.7°, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form B,of Compound X which has an XRPD pattern with specific peaks at about2-theta=4.2, 6.6, 7.7, 9.8, 13.1, 13.7, 18.6, 20.0, 26.5, 28.8°,measured using CuKα.

According to the invention there is provided crystalline form, Form B,of Compound X which has an XRPD pattern substantially the same as theXRPD shown in Figure C, measured using CuKα radiation.

According to the invention there is provided crystalline form, Form B,of Compound X which has an XRPD pattern with at least one specific peakat 2-theta=4.2° plus or minus 0.2° 2-theta, measured using CuKαradiation.

According to the invention there is provided a crystalline form, Form B,of Compound X which has an XRPD pattern with at least one specific peakat 2-theta=7.7° plus or minus 0.2° 2-theta, measured using CuKαradiation.

According to the invention there is provided a crystalline form, Form B,of Compound X which has an XRPD pattern with at least two specific peaksat 2-theta=4.2° and 7.7° wherein said values may be plus or minus 0.2°2-theta, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form B,of Compound X which has an XRPD pattern with specific peaks at2-theta=4.2, 6.6, 7.7, 9.8, 13.1, 13.7, 18.6, 20.0, 26.5, 28.8° whereinsaid values may be plus or minus 0.2° 2-theta, measured using CuKαradiation.

DSC analysis of Compound X, Form B is shown in Figure D.

As a further example, the compound of Example 12A, Tosylate Salt Y,exhibits crystallinity and four crystalline forms, Form A, Form B, FormC and Form D have been identified and have been obtained using theconditions described hereinafter in the experimental section.

Polymorphic Form a of Tosylate Salt Y

Accordingly, a further aspect of the invention is Form A of TosylateSalt Y (Example 12A).

According to the invention there is provided a crystalline form, Form Aof Tosylate Salt Y, which has an XRPD pattern with at least one specificpeak at about 2-theta=13.4°, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form Aof Tosylate Salt Y, which has an XRPD pattern with at least one specificpeak at about 2-theta=14.3°, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form Aof Tosylate Salt Y, which has an XRPD pattern with at least two specificpeaks at about 2-theta=13.4° and 14.3°, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form Aof Tosylate Salt Y, which has an XRPD pattern with specific peaks atabout 2-theta=11.7, 12.2, 13.4, 14.3, 17.3, 20.2, 21.4, 23.6, 23.7,24.4°, measured using CuKα radiation.

According to the invention there is provided crystalline form, Form A ofTosylate Salt Y, which has an XRPD pattern substantially the same as theXRPD pattern shown in Figure E.

According to the invention there is provided crystalline form, Form A ofTosylate Salt Y, which has an XRPD pattern with at least one specificpeak at 2-theta=13.4° plus or minus 0.2° 2-theta, measured using CuKαradiation.

According to the invention there is provided a crystalline form, Form Aof Tosylate Salt Y, which has an XRPD pattern with at least one specificpeak at 2-theta=14.3° plus or minus 0.2° 2-theta, measured using CuKαradiation.

According to the invention there is provided a crystalline form, Form Aof Tosylate Salt Y, which has an XRPD pattern with at least two specificpeaks at 2-theta=13.4° and 14.3° wherein said values may be plus orminus 0.2° 2-theta, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form Aof Tosylate Salt Y, which has an XRPD pattern with specific peaks at2-theta=11.7, 12.2, 13.4, 14.3, 17.3, 20.2, 21.4, 23.6, 23.7, 24.4°wherein said values may be plus or minus 0.2° 2-theta, measured usingCuKα radiation.

DSC analysis of Form A of Tosylate Salt Y shows a melting endotherm withan onset of about 165.7° C. and a peak at about 170.8° C. (Figure F).

Thus DSC analysis shows Form A of Tosylate Salt Y is a high meltingsolid with an onset of melting at about 165.7° C. and a peak at about170.8° C.

Polymorphic Form B of Tosylate Salt Y

A further aspect of the invention is Form B of Tosylate Salt Y.

According to the invention there is provided a crystalline form, Form Bof Tosylate Salt Y, which has an XRPD pattern with at least one specificpeak at about 2-theta=7.1°, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form Bof Tosylate Salt Y, which has an XRPD pattern with at least one specificpeak at about 2-theta=9.2°, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form Bof Tosylate Salt Y, which has an XRPD pattern with at least two specificpeaks at about 2-theta=7.1° and 9.2°, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form Bof Tosylate Salt Y, which has an XRPD pattern with specific peaks atabout 2-theta=7.1, 9.2, 11.8, 14.2, 19.4, 20.4, 20.9, 22.5, 23.9, 25.2°,measured using CuKα radiation.

According to the invention there is provided crystalline form, Form B ofTosylate Salt Y, which has an XRPD pattern substantially the same as theXRPD pattern shown in Figure G.

According to the invention there is provided crystalline form, Form B ofTosylate Salt Y, which has an XRPD pattern with at least one specificpeak at 2-theta=7.1° plus or minus 0.2° 2-theta, measured using CuKαradiation.

According to the invention there is provided a crystalline form, Form Bof Tosylate Salt Y, which has an XRPD pattern with at least one specificpeak at 2-theta=9.2° plus or minus 0.2° 2-theta, measured using CuKαradiation.

According to the invention there is provided a crystalline form, Form Bof Tosylate Salt Y, which has an XRPD pattern with at least two specificpeaks at 2-theta=7.1° and 9.2° wherein said values may be plus or minus0.2° 2-theta.

According to the invention there is provided a crystalline form, Form Bof Tosylate Salt Y, which has an XRPD pattern with specific peaks at2-theta=7.1, 9.2, 11.8, 14.2, 19.4, 20.4, 20.9, 22.5, 23.9, 25.2°wherein said values may be plus or minus 0.2° 2-theta, measured usingCuKα radiation.

DSC analysis of Form B of Tosylate Salt Y shows a melting endotherm withan onset of about 140.0° C. and a peak at about 146.2° C. (Figure H).

Thus DSC analysis shows Form B of Tosylate Salt Y is a solid with anonset of melting at about 140.0° C. and a peak at about 146.2° C.

Polymorphic Form D of Tosylate Salt Y

A further aspect of the invention is Form D of Tosylate Salt Y.

According to the invention there is provided a crystalline form, Form Dof Tosylate Salt Y, which has an XRPD pattern with at least one specificpeak at about 2-theta=0.4°, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form Dof Tosylate Salt Y, which has an XRPD pattern with at least one specificpeak at about 2-theta=5.6°, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form Dof Tosylate Salt Y, which has an XRPD pattern with at least two specificpeaks at about 2-theta=4.4° and 5.6°, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form Dof Tosylate Salt Y, which has an XRPD pattern with specific peaks atabout 2-theta=4.4, 5.6, 8.8, 16.8, 19.1, 19.7, 21.9, 22.3, 24.8, 26.9°,measured using CuKα radiation.

According to the invention there is provided crystalline form, Form D ofTosylate Salt Y, which has an XRPD pattern substantially the same as theXRPD pattern shown in Figure I.

According to the invention there is provided crystalline form, Form D ofTosylate Salt Y, which has an XRPD pattern with at least one specificpeak at 2-theta=4.4° plus or minus 0.2° 2-theta, measured using CuKαradiation.

According to the invention there is provided a crystalline form, Form Dof Tosylate Salt Y, which has an XRPD pattern with at least one specificpeak at 2-theta=5.6° plus or minus 0.2° 2-theta, measured using CuKαradiation.

According to the invention there is provided a crystalline form, Form Dof Tosylate Salt Y, which has an XRPD pattern with at least two specificpeaks at 2-theta=4.4° and 5.6° wherein said values may be plus or minus0.2° 2-theta, measured using CuKα radiation.

According to the invention there is provided a crystalline form, Form Dof Tosylate Salt Y, which has an XRPD pattern with specific peaks at2-theta=4.4, 5.6, 8.8, 16.8, 19.1, 19.7, 21.9, 22.3, 24.8, 26.9° whereinsaid values may be plus or minus 0.2° 2-theta, measured using CuKαradiation.

DSC analysis of Form D of Tosylate Salt Y shows a melting endotherm withan onset of about 116.5° C. and a peak at about 122.3° C. (Figure J).

Thus DSC analysis shows Form D of Tosylate Salt Y s a solid with anonset of melting at about 116.5° C. and a peak at about 122.3° C.

When it is stated that the present invention relates to a crystallineform of Form A or Form B of Compound X, or Form A, Form B or Form D ofTosylate Salt Y, the degree of crystallinity is conveniently greaterthan about 60%, more conveniently greater than about 80%, preferablygreater than about 90% and more preferably greater than about 95%. Mostpreferably the degree of crystallinity is greater than about 98%.

It will be understood that the 2-theta values of the X-ray powderdiffraction pattern may vary slightly from one machine to another orfrom one sample to another, and so the values quoted are not to beconstrued as absolute.

It is known that an X-ray powder diffraction pattern may be obtainedwhich has one or more measurement errors depending on measurementconditions (such as equipment or machine used). In particular, it isgenerally known that intensities in an X-ray powder diffraction patternmay fluctuate depending on measurement conditions. Therefore it shouldbe understood that Compound X, Form A and Form B, and Tosylate Salt Y,Form A, Form B and Form D, of the invention are not limited to thecrystals that provide X-ray powder diffraction patterns identical to theX-ray powder diffraction pattern shown in Figures A, C, E, G and I, andany crystals providing X-ray powder diffraction pattern shown in FiguresA, C, E, G and I fall within the scope of the present invention. Aperson skilled in the art of X-ray powder diffraction is able to judgethe substantial identity of X-ray powder diffraction patterns.

Persons skilled in the art of X-ray powder diffraction will understandthat the relative intensity of peaks can be affected by, for example,grains above 30 microns in size and non-unitary aspect ratios, which mayaffect analysis of samples. The skilled person will also understand thatthe position of reflections can be affected by the precise height atwhich the sample sits in the diffractometer and the zero calibration ofthe diffractometer. The surface planarity of the sample may also have asmall effect. Hence the diffraction pattern data presented are not to betaken as absolute values. (Jenkins, R & Snyder, R. L. ‘Introduction toX-Ray Powder Diffractometry’ John Wiley & Sons 1996; Bunn. C. W. (1948),Chemical Crystallography, Clarendon Press, London; Klug, H. P. &Alexander, L. E. (1974), X-Ray Diffraction Procedures).

Generally, a measurement error of a diffraction angle in an X-ray powderdiffractogram is approximately plus or minus 0.2° 2-theta, and suchdegree of a measurement error should be taken into account whenconsidering the X-ray powder diffraction pattern in Figures A, C, E, Gand I and when reading Tables A to E (see Examples 12 and 12A).Furthermore, it should be understood that intensities might fluctuatedepending on experimental conditions and sample preparation (preferredorientation).

The compounds of Formula (I) include one or more chiral centres. To theextent a structure or chemical name in this specification does notindicate chirality, the structure or name is intended to encompass anysingle stereoisomer (i.e. any single chiral isomer) corresponding tothat structure or name, as well as any mixture of stereoisomers (e.g. aracemate). It is well-known in the art how such optically-active formscan be prepared. For example, a single stereoisomer can be obtained byisolating it from a mixtures of isomers (e.g. a racemate) using, forexample, chiral chromatographic separation. In other embodiments, asingle stereoisomer is obtained through direct synthesis from, forexample, a chiral starting material.

Compounds of Formula (I), where R² is fluoro, may for example beprepared by the reaction of a compound of Formula (II) or a saltthereof:

where R³ and R⁴ are as defined in any of the embodiments herein, with acompound of Formula (III):

or a salt thereof, where R¹ is as defined in any of the embodimentsherein. The reaction is conveniently performed in a suitable solvent(for example acetic acid) at a suitable temperature (for example atemperature of about 25 to 100° C.).

Compounds of Formula (II) and (III), and salts thereof, are thereforeuseful as intermediates in the preparation of compounds of Formula (I),where R² is fluoro, and provide a further embodiment.

In any of the embodiments where a compound of Formula (II) or (III) or asalt thereof is mentioned it is to be understood that such salts do notneed to be pharmaceutically acceptable salts.

The compound of Formula (II) may for example be prepared by the reactionof a compound of Formula (IV):

or a salt thereof, where R³ and R⁴ are as defined in any of theembodiments herein, with a dialkyl acetal of DMF (for example1,1-dimethoxy-N,N-dimethylmethanamine).

The compound of Formula (IV) may for example be prepared by the reactionof a compound of Formula (V):

where R³ and R⁴ are as defined in any of the embodiments herein, with aweak base (for example aqueous ammonia) under high temperature andpressure conditions (for example a temperature of about 80 to 100° C.and a pressure of about 3 to 15 bar).

The compound of Formula (V) may for example be prepared by the reactionof a compound of Formula (VI):

or a salt thereof, where R³ is as defined in any) of the embodimentsherein, with R⁴—Br, where R⁴ is as defined in any of the embodimentsherein, in the presence of a suitable base (for example potassiumcarbonate) and solvent (for example dimethylformamide) and at a suitabletemperature (for example about 80° C.).

The compound of Formula (III) may for example be prepared by thereaction of a compound of Formula (VII):

where R¹ is as defined in any of the embodiments herein and PG is asuitable protecting group (for example tert-butyloxycarbonyl (BOC)),with a suitable deprotecting agent (for example HCl in dioxane) and in asuitable solvent (for example DCM).

The compound of Formula (VII) may for example be prepared by thereaction of a compound of Formula (VIII):

or a salt thereof, with a compound of Formula (IX):

or a salt thereof, where R¹ is as defined in any of the embodimentsherein and PG is a suitable protecting group (for exampletert-butyloxycarbonyl (BOC)), in the presence of a suitable reagent andbase for peptide coupling (for example HATU and DIPEA respectively) anda suitable solvent (for example DMF).

Compounds of Formula (I), where R² is C₁₋₂ alkoxy, may for example beprepared by the reaction of a compound of Formula (X):

or a salt thereof, where R^(2′) is C₁₋₂ alkyl and R¹, R³ and R⁴ are asdefined in any of the embodiments herein, with a compound of Formula(XI):

or a salt thereof, in the presence of a suitable reagent and base forpeptide coupling (for example HATU and DIPEA respectively) and asuitable solvent (for example DMF) and at a suitable temperature (forexample room temperature). In one embodiment, R^(2′) is methyl. In oneembodiment, R^(2′) is ethyl.

Compounds of Formula (X) and (XI), and salts thereof, are thereforeuseful as intermediates in the preparation of compounds of Formula (I),where R² is C₁₋₂ alkoxy, and provide a further embodiment.

In any of the embodiments where a compound of Formula (X) or (XI) or asalt thereof is mentioned it is to be understood that such salts do notneed to be pharmaceutically acceptable salts.

The compound of Formula (X) may for example be prepared by the reactionof a compound of Formula (XII):

or a salt thereof, where R^(2′), R³ and R⁴ are as defined in any of theembodiments herein, with a compound of Formula (XIII):

or a salt thereof, where R¹ is as defined in any of the embodimentsherein, in the presence of a suitable peptide coupling reagent (forexample PyBOP), a strong organic base (for example DBU) and a suitablesolvent (for example MeCN).

The compound of Formula (XII) may for example be prepared by thereaction of a compound of Formula (XIV):

where R^(2′) and R³ are as defined in any of the embodiments herein,with KOR⁴, or another suitable alkali metal alkoxide, at a suitabletemperature (for example about 60 to 100° C.), where R⁴ is as defined inany of the embodiments herein.

The compound of Formula (XIV) may for example be prepared by thereaction of a compound of Formula (XV):

where R³ is as defined in any of the embodiments herein, with a suitablealkali metal alkoxide (for example NaOR^(2′)) at a suitable temperature(for example room temperature), where R^(2′) is as defined in any of theembodiments herein.

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. For example compounds of Formula (I) may beconverted into further compounds of Formula (I) by standard aromaticsubstitution reactions or by conventional functional groupmodifications. Such reactions and modifications include, for example,introduction of a substituent by means of an aromatic substitutionreaction, reduction of substituents, alkylation of substituents andoxidation of substituents. The reagents and reaction conditions for suchprocedures are well known in the chemical art.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

Compounds of Formula (I), (II) and (III), and any intermediates used tomake these, can be prepared by methods similar to those shown in theExamples section.

Biological Assays

The following assay was used to measure the effects of the compounds ofthe invention.

3 different KIT cDNA encoding for the exon11 deletion (557-558) and asecondary mutation (V654A, T670I, D816H) from Genescript were clonedinto pLVX-IRES Puro vector (Clontech). Lentiviral particles weregenerated using Trans-lentiviral ORF packaging kit (TLP 5918) fromThermo Scientific (Waltham, Mass.) in HEK293-T/17 cells, according tothe manufacturer's instructions.

Tel-KDR myc was cloned into pBCS2004, a retroviral vector, wherein KDR(K790-V1356) is fused to the C-terminus of Tel. Retroviral particleswere generated in HEK293T cells. The Tel-KDR plasmid was co-transfectedwith helper viruses (gag-Pol and VSV-G) into HEK293T cells using calciumphosphate and the virus was harvested 72 h after transfection.

Exponentially grown Ba/F3 cells (1.5×106 cells in 2 ml medium) wereinfected with 2 ml of viral suspension in a 6-well plate in the presenceof mIL-3 (10 ng/ml) and polybrene (4 μg/ml) (Sigma Aldrich, St. Louis,Mo.) and incubated for 24 h. After 24 h, the cells were centrifuged andthe viral supernatant was discarded. The cells were then re-suspended infresh medium and allowed to recover for another day. The following day,the cells were seeded in complete medium without murine IL-3. After aweek or two, when cells started proliferating, a selection was carriedout by gradually increasing the puromycin concentration to 0.5 ug/ml.Once the cells were growing exponentially in puromycin, batches of cellswere frozen down for banking.

The impact of KIT inhibitors on the viability of Ba/F3 expressing KITmutations was determined using an MTS assay, which is a colorimetricsensitive quantification of viable cells in proliferation andcytotoxicity assay. In the MTS assay3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) inthe presence of phenazine methosulfate (PMS) was used. The mitochondrialreductase forms a formazan which absorbs at 490 nm. Cells in exponentialgrowth phase were added to 384-well plates containing pre-dispensedcompounds (top concentration 10 uM, 10-point curve). The cells wereincubated for 72 h at 37° C. and 5% CO₂. After 72 h, MTS reagent wasadded to the plates and incubated an additional 2 h at 37° C. beforemeasuring the absorbance at 490 nm on a Tecan microplate reader usingMagellan Software (Tecan Trading AG, Switzerland).

The absorbances were normalized as follows: (Read-Day0 control)/(Day3control−Day0 control)*100. The GI₅₀ values were generated using GenedataScreener software (Genedata Lexington, Mass.). A non-linear regressionwith constraints for top and bottom between 100 and −100 and noconstraint on the Hill coefficient was used to generate GI₅₀ values. TheGI₅₀ values reported below are the calculated mean result of at least 3biological replicates across all the cell lines tested.

The following data was generated for the Examples (the data below may bea result from a single experiment or an average of multiple repeatexperiments):

Ba/F3- Ba/F3- Ba/F3- TEL- T670I V654A D816H KDR Ba/F3-Parental GI50 GI50GI50 GI50 Example GI50 (μM) (μM) (μM) (μM) (μM) 1 10.000 0.162 0.0070.141 10.000 2 10.000 0.049 0.004 0.022 2.496 3 1.466 0.061 0.011 0.0421.838 4 1.724 0.049 0.012 0.045 2.218 5 1.871 0.591 0.041 0.138 6.179 62.053 0.091 0.013 0.063 2.655 7 10.000 0.073 0.007 0.079 3.193 8 2.5510.032 0.015 0.044 2.149 9 1.707 0.127 0.012 0.105 2.334 10 10.000 0.6400.007 0.065 9.485 11 10.000 0.036 0.004 0.027 2.476 12 10.000 0.0150.002 0.007 1.303 13 10.000 0.208 0.009 0.024 3.261 14 10.000 0.1590.015 0.038 5.404 15 10.000 0.254 0.011 0.035 4.181 16 10.000 0.5020.012 0.090 9.358 17 10.000 0.627 0.020 0.088 10.000 18 10.000 0.0660.003 0.021 6.014 19 10.000 0.034 0.007 0.056 10.000 20 9.961 0.0530.008 0.030 3.393 21 10.000 0.068 0.002 0.025 10.000 22 10.000 0.1060.003 0.048 5.346

The data shows that the compounds of the invention inhibit KIT carryingboth primary and secondary KIT mutations simultaneously, andfurthermore, are selective against KDR. In some embodiments,pharmaceutically acceptable salts of the compounds of Formula (I)convert to the free base form in vivo. For example, the tosylate salt ofExample 12 (also referred to herein as Example 12A and Tosylate Salt Y)converts to the free base in vivo and it is the free base, rather thanthe tosylate salt, that passes through the cell membrane. Administrationof the tosylate salt would therefore lead to the free base activityexemplified above for Example 12.

Compounds may be further selected on the basis of further biological orphysical properties which may be measured by techniques known in the artand which may be used in the assessment or selection of compounds fortherapeutic or prophylactic application.

As a result of their KIT inhibitory activity, the compounds of Formula(I), and pharmaceutically acceptable salts thereof are expected to beuseful in therapy.

We have found that the compounds of Formula (I) possess potentanti-tumour activity which it is believed is obtained by way ofinhibition of both wildtype KIT and KIT mutants. We have also found thatthe compounds of Formula (I) may also act partly as an immune-oncologydrug.

The term “therapy” is intended to have its normal meaning of dealingwith a disease in order to entirely or partially relieve one, some orall of its symptoms, or to correct or compensate for the underlyingpathology. The term “therapy” also includes “prophylaxis” unless thereare specific indications to the contrary. The terms “therapeutic” and“therapeutically” should be interpreted in a corresponding manner.

The term “prophylaxis” is intended to have its normal meaning andincludes primary prophylaxis to prevent the development of the diseaseand secondary prophylaxis whereby the disease has already developed andthe patient is temporarily or permanently protected against exacerbationor worsening of the disease or the development of new symptomsassociated with the disease.

The term “treatment” is used synonymously with “therapy”. Similarly theterm “treat” can be regarded as “applying therapy” where “therapy” is asdefined herein.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in therapy.

In one embodiment there is provided the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment of adisease mediated by KIT. In one embodiment, the disease mediated by KITis cancer. In one embodiment the cancer is selected from the groupconsisting of gastrointestinal stromal tumour (GIST), melanoma, lungcancers, glioblastoma, leukemias, testicular carcinomas and head andneck cancers. Lung cancers include small cell lung cancer (SCLC),adenocarcinomas and squamous carcinomas of the lung. Leukemias includeacute myeloid leukaemia (AML) and mast cell leukemias.

In one embodiment the cancer is a gastrointestinal stromal tumour. GISTis a type of tumour that occurs in the gastrointestinal tract, mostcommonly in the stomach or small intestine.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer.

In one embodiment there is provided the use of the compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament for the treatment of a disease mediated by KIT. In oneembodiment, the disease mediated by KIT is cancer. In one embodiment,the cancer is selected from the group consisting of gastrointestinalstromal tumors (GIST), melanoma, lung cancers, glioblastoma, leukemias,testicular carcinomas and head and neck cancers. Lung cancers includesmall cell lung cancer (SCLC), adenocarcinomas and squamous carcinomasof the lung. Leukemias include acute myeloid leukaemia (AML) and mastcell leukemias.

In one embodiment there is provided the use of the compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament for the treatment of cancer.

In one embodiment there is provided a method for treating a disease inwhich inhibition of KIT is beneficial in a warm-blooded animal in needof such treatment, which comprises administering to said warm-bloodedanimal a therapeutically effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof. In one embodiment, thedisease is cancer. In one embodiment, the cancer is selected from thegroup consisting of gastrointestinal stromal tumors (GIST), melanomas,lung cancers, glioblastoma, leukemias, testicular carcinomas and headand neck cancers. Lung cancers include small cell lung cancer (SCLC),adenocarcinomas and squamous carcinomas of the lung. Leukemias includeacute myeloid leukaemia (AML) and mast cell leukemias.

In one embodiment the cancer is gastrointestinal stromal tumour.

The term “therapeutically effective amount” refers to an amount of acompound of Formula (I) as described in any of the embodiments hereinwhich is effective to provide “therapy” in a subject, or to “treat” adisease or disorder in a subject. In the case of cancer, thetherapeutically effective amount may cause any of the changes observableor measurable in a subject as described in the definition of “therapy”,“treatment” and “prophylaxis” above. For example, the effective amountcan reduce the number of cancer or tumour cells; reduce the overalltumour size; inhibit or stop tumour cell infiltration into peripheralorgans including, for example, the soft tissue and bone; inhibit andstop tumour metastasis; inhibit and stop tumour growth; relieve to someextent one or more of the symptoms associated with the cancer; reducemorbidity and mortality; improve quality of life; or a combination ofsuch effects. An effective amount may be an amount sufficient todecrease the symptoms of a disease responsive to inhibition of KITactivity. For cancer therapy, efficacy in-vivo can, for example, bemeasured by assessing the duration of survival, time to diseaseprogression (TP), the response rates (RR), duration of response, and/orquality of life. As recognized by those skilled in the art, effectiveamounts may vary depending on route of administration, excipient usage,and co-usage with other agents. For example, where a combination therapyis used, the amount of the compound of Formula (I) or pharmaceuticallyacceptable salt described in this specification and the amount of theother pharmaceutically active agent(s) are, when combined, jointlyeffective to treat a targeted disorder in the animal patient. In thiscontext, the combined amounts are in a “therapeutically effectiveamount” if they are, when combined, sufficient to decrease the symptomsof a disease responsive to inhibition of KIT activity as describedabove. Typically, such amounts may be determined by one skilled in theart by, for example, starting with the dosage range described in thisspecification for the compound of Formula (I) or pharmaceuticallyacceptable salt thereof and an approved or otherwise published dosagerange(s) of the other pharmaceutically active compound(s).

“Warm-blooded animals” include, for example, humans.

In one embodiment there is provided a method for treating cancer in awarm-blooded animal in need of such treatment, which comprisesadministering to said warm-blooded animal a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof. In one embodiment, said cancer is selected from the groupconsisting of gastrointestinal stromal tumors (GIST), melanoma, lungcancers, glioblastoma, leukemias, testicular carcinomas and head andneck cancers. Lung cancers include small cell lung cancer (SCLC),adenocarcinomas and squamous carcinomas of the lung. Leukemias includeacute myeloid leukaemia (AML) and mast cell leukemias.

In one embodiment the cancer is gastrointestinal stromal tumour.

The anti-cancer treatment described in this specification may be usefulas a sole therapy, or may involve, in addition to administration of thecompound of Formula (I), or a pharmaceutically acceptable salt thereof,conventional surgery, radiotherapy or chemotherapy; or a combination ofsuch additional therapies. Such conventional surgery, radiotherapy orchemotherapy may be administered simultaneously, sequentially orseparately to treatment with the compound of Formula (I) or apharmaceutically acceptable salt thereof.

Where a combination therapy is administered “simultaneously”, thisincludes treatment of a patient with a single dosage form (e.g. atablet) comprising both a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof and an additional anti-cancer substance; andalso simultaneous dosing of separate dosage forms each separatelycomprising one of the respective combination partners.

Where a combination therapy is administered “sequentially” or“separately”, this includes treatment of a patient with a first dosageform (e.g. a tablet) comprising a compound of Formula (I), or apharmaceutically acceptable salt thereof, followed by treatment of thesame patient with a second dosage form comprising an additionalanti-cancer substance; or treatment of a patient with a single dosageform (e.g. a tablet) comprising a particular anti-cancer substance,followed by treatment of the same patient with a second dosage formcomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof. The interval between the sequential or separate doses maybe judged by a skilled practitioner with reference to the information inthis specification.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof is administered before surgery.

Administration of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, before surgery to entirely or partially removea cancer may be referred to as “neo-adjuvant therapy”. In such ascenario, the goal of administering the compound of Formula (I), or apharmaceutically acceptable salt thereof is generally to reduce the sizeof the target tumour in order to increase the chances of a successfulresection. As such, the length of time the compound of Formula (I), or apharmaceutically acceptable salt thereof is dosed before surgery may bejudged by a skilled practitioner with reference to the informationwithin this specification.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof is administered after surgery.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof is administered in combination with at least oneadditional anti-cancer substance.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof is administered simultaneously, sequentially orseparately with at least one additional anti-cancer substance.

The anti-cancer treatment defined herein may be applied as a soletherapy or may involve, in addition to the compounds of thespecification, conventional surgery or radiotherapy or chemotherapy.Such chemotherapy may include one or more of the following categories ofanti-tumour agents:

(i) inhibitors of growth factor function and their downstream signallingpathways: included are Ab modulators of any growth factor or growthfactor receptor targets, reviewed by Stem et al. Critical Reviews inOncology/Haematology, 2005, 54, pp 11-29); also included are smallmolecule inhibitors of such targets, for example kinaseinhibitors—examples include the anti-erbB2 antibody trastuzumab[Herceptin™], the anti-EGFR antibody panitumumab, the anti-EGFR antibodycetuximab [Erbitux, C225] and tyrosine kinase inhibitors includinginhibitors of the erbB receptor family, such as epidermal growth factorfamily receptor (EGFR/erbB1) tyrosine kinase inhibitors such asgefitinib or erlotinib, erbB2 tyrosine kinase inhibitors such aslapatinib, and mixed erb1/2 inhibitors such as afatanib; similarstrategies are available for other classes of growth factors and theirreceptors, for example inhibitors of the hepatocyte growth factor familyor their receptors including c-met and ron; inhibitors of the insulinand insulin growth factor family or their receptors (IGFR, IR)inhibitors of the platelet-derived growth factor family or theirreceptors (PDGFR), and inhibitors of signalling mediated by otherreceptor tyrosine kinases such as c-kit, AnLK, and CSF-1R; also includedare modulators which target signalling proteins in the PI3-kinasesignalling pathway, for example, inhibitors of PI3-kinase isoforms suchas PI3K-α/β/γ and ser/thr kinases such as AKT, mTOR (such as AZD2014),PDK, SGK, PI4K or PIP5K; also included are inhibitors ofserine/threonine kinases not listed above, for example raf inhibitorssuch as vemurafenib, MEK inhibitors such as selumetinib (AZD6244), Ablinhibitors such as imatinib or nilotinib, Btk inhibitors such asibrutinib, Syk inhibitors such as fostamatinib, aurora kinase inhibitors(for example AZD1152), inhibitors of other ser/thr kinases such as JAKs,STATs and IRAK4, and cyclin dependent kinase inhibitors for exampleinhibitors of CDK1, CDK7, CDK9 and CDK4/6 such as palbociclib;

(ii) modulators of apoptotic and cell death pathways such as Bcl familymodulators (e.g. ABT-263/Navitoclax, ABT-199);

(iii) immunotherapy approaches, including for example ex-vivo andin-vivo approaches to increase the immunogenicity of patient tumourcells, such as transfection with cytokines such as interleukin 2,interleukin 4 or granulocyte-macrophage colony stimulating factor,approaches to decrease T-cell anergy, approaches using transfectedimmune cells such as cytokine-transfected dendritic cells, approachesusing cytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies. Specific examples include monoclonalantibodies targeting PD-1 (e.g. BMS-936558) or CTLA4 (e.g. ipilimumaband tremelimumab).

Therefore, in one embodiment there is provided a compound of Formula(I), or a pharmaceutically acceptable salt thereof, and at least oneadditional anti-tumour substance, for use in the treatment of cancer. Inone embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof is administered in combination with anadditional anti-tumour substance. In one embodiment there is oneadditional anti-tumour substance. In one embodiment there are twoadditional anti-tumour substances. In one embodiment there are three ormore additional anti-tumour substances.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least one additionalanti-tumour substance for use in the simultaneous, separate orsequential treatment of cancer. In one embodiment there is provided acompound of Formula (I), or a pharmaceutically acceptable salt thereof,for use in the treatment of cancer, where the compound of Formula (I),or a pharmaceutically acceptable salt thereof, is administeredsimultaneously, separately or sequentially with an additionalanti-tumour substance.

In one embodiment there is provided a method of treating cancer in awarm-blooded animal who is in need of such treatment, which comprisesadministering to said warm-blooded animal a compound of Formula (I), ora pharmaceutically acceptable salt thereof and at least one additionalanti-tumour substance, wherein the amounts of the compound of Formula(I), or a pharmaceutically acceptable salt thereof, and the additionalanti-tumour substance are jointly effective in producing an anti-cancereffect.

In one embodiment there is provided a method of treating cancer in awarm-blooded animal who is in need of such treatment, which comprisesadministering to said warm-blooded animal a compound of Formula (I), ora pharmaceutically acceptable salt thereof, and simultaneously,separately or sequentially administering at least one additionalanti-tumour substance to said warm-blooded animal, wherein the amountsof the compound of Formula (I), or pharmaceutically acceptable saltthereof, and the additional anti-tumour substance are jointly effectivein producing an anti-cancer effect.

In any embodiment the additional anti-tumour substance is selected fromthe group consisting of one or more of the anti-tumour substances listedunder points (i)-(iii) above.

In one embodiment there is provided a pharmaceutical compositioncomprising a compound of Formula (I) and at least one additionalanti-tumour substance, for use in the treatment of cancer. In oneembodiment the pharmaceutical composition also comprises at least onepharmaceutically acceptable diluent or carrier. In one embodiment theanti-tumour substance is an anti-neoplastic agent.

According to a further embodiment there is provided a kit comprising:

a) A compound of Formula (I), or a pharmaceutically acceptable saltthereof, in a first unit dosage form:

b) A further additional anti-tumour substance in a further unit dosageform;

c) Container means for containing said first and further unit dosageforms; and optionally

d) Instructions for use.

The compounds of Formula (I), and pharmaceutically acceptable saltsthereof, may be administered as pharmaceutical compositions, comprisingone or more pharmaceutically acceptable diluents or carriers.

Therefore, in one embodiment there is provided a pharmaceuticalcomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablediluent or carrier. The compositions may be in a form suitable for oraluse (for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous or intramusculardosing), or as a suppository for rectal dosing. The compositions may beobtained by conventional procedures using conventional pharmaceuticalexcipients, well known in the art. Thus, compositions intended for oraluse may contain, for example, one or more colouring, sweetening,flavouring and/or preservative agents.

In one embodiment there is provided a pharmaceutical compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and at least one pharmaceutically acceptable diluent orcarrier, for use in therapy.

In one embodiment there is provided a pharmaceutical compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and at least one pharmaceutically acceptable diluent orcarrier, for use in the treatment of cancer. In one embodiment, saidcancer is selected from the group consisting of gastrointestinal stromaltumors (GIST), melanoma, lung cancers, glioblastoma, leukemias,testicular carcinomas and head and neck cancers. Lung cancers includesmall cell lung cancer (SCLC), adenocarcinomas and squamous carcinomasof the lung. Leukemias include acute myeloid leukaemia (AML) and mastcell leukemias.

The compound of Formula (I) will normally be administered to awarm-blooded animal at a unit dose within the range 2.5-5000 mg/m² bodyarea of the animal, or approximately 0.05-100 mg/kg, and this normallyprovides a therapeutically-effective dose. A unit dose form such as atablet or capsule will usually contain, for example 0.1-500 mg of activeingredient. The daily dose will necessarily be varied depending upon thehost treated, the particular route of administration, any therapiesbeing co-administered, and the severity of the illness being treated.Accordingly the practitioner who is treating any particular patient maydetermine the optimum dosage.

EXAMPLES

Aspects of the present disclosure can be further defined by reference tothe following non-limiting examples, which describe in detailpreparation of certain compounds and intermediates of the presentdisclosure and methods for using compounds of the present disclosure. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, can be practiced without departing fromthe scope of the present disclosure.

Unless stated otherwise:

(i) all syntheses were carried out at ambient temperature, i.e. in therange 17 to 25° C. and under an atmosphere of an inert gas such asnitrogen unless otherwise stated;

(ii) evaporations were carried out by rotary evaporation or utilisingGenevac equipment or Biotage v10 evaporator in vacuo and work upprocedures were carried out after removal of residual solids byfiltration;

(iii) flash column chromatography was performed on Merck Kieselgelsilica (Art. 9385) or on reversed phase silica (Fluka silica gel 90 C18)or on Silicycle cartridges (40-63 μm silica, 4 to 330 g weight) or onGrace resolv cartridges (4-120 g) or on RediSep Rf 1.5 Flash columns oron RediSep Rf high performance Gold Flash columns (150-415 g weight) oron RediSep Rf Gold C18 Reversed-phase columns (20-40 μm silica) eithermanually or automated using an Isco CombiFlash Companion system orsimilar system;

(iv) preparative reverse phase HPLC was performed on a Waters instrument(600/2700 or 2525) fitted with a ZMD or ZQ ESCi mass spectrometers and aWaters X-Terra or a Waters X-Bridge or a Waters SunFire reverse-phasecolumn (C-18, 5 microns silica, 19 mm or 50 mm diameter, 100 mm length,flow rate of 40 mL/minute) using decreasingly polar mixtures of water(containing 1% ammonia) and acetonitrile or decreasingly polar mixturesof water (containing 0.1% formic acid) and acetonitrile as eluents;

(v) chiral HPLC methods were carried out using a Gilson GX-281 HPLC anda Daicel CHIRALPAK IC (2×25 cm, 5 um) or Daicel CHIRALPAK IF (2×25 cm, 5um); in general a flow rate of between 10-350 ml/minute and detectionwas by UV absorbance at a typical wavelength of 254 nm. A sampleconcentration of about 1-100 mg/ml was used in a suitable solventmixture with an injection volume of between 0.5-10 ml and run time ofbetween 10-150 minutes and a typical oven temperature of 25-35° C.;analytical chiral HPLC methods were carried out using Shimadzu UFLC anda Daicel CHIRALPAK IC-3 (50×4.6 mm 3 um) or Daicel CHIRALPAK IF-3(50×4.6 mm 3 um); in general a flow rate of 1 ml/minute and detectionwas by UV absorbance at a typical wavelength of 254 nm. A sampleconcentration of about 1 mg/ml was used in a suitable solvent such asEtOH with an injection volume of about 10 μl and run time of between10-60 minutes and a typical oven temperature of 25-35° C.;

(vi) yields, where present, are not necessarily the maximum attainable;

(vii) in general, the structures of end products of the compounds ofFormula (I) were confirmed by nuclear magnetic resonance (NMR)spectroscopy; NMR chemical shift values were measured on the delta scale[proton magnetic resonance spectra were determined using a Bruker Avance500 (500 MHz), Bruker Avance 400 (400 MHz), Bruker Avance 300 (300 MHz)or Bruker DRX (300 MHz) instrument]; measurements were taken at ambienttemperature unless otherwise specified; the following abbreviations havebeen used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;dd, doublet of doublets; ddd, doublet of doublet of doublet; dt, doubletof triplets; bs, broad signal;

(viii) in general, end products of Formula (I) were also characterizedby mass spectroscopy following liquid chromatography (LCMS or UPLC); ingeneral, reverse-phase C18 silica was used with a flow rate of 1mL/minute and detection was by Electrospray Mass Spectrometry and by UVabsorbance recording a wavelength range of 220-320 nm. Analytical UPLCwas performed on CSH C18 reverse-phase silica, using a Waters XSelectCSH C18 column with dimensions 2.1×50 mm and particle size 1.7 micron).Gradient analysis was employed using decreasingly polar mixtures aseluent, for example decreasingly polar mixtures of water (containing0.1% formic acid or 0.1% ammonia) as solvent A and acetonitrile assolvent B. A typical 2 minute analytical UPLC method would employ asolvent gradient over 1.3 minutes, at approximately 1 mL per minute,from a 97:3 mixture of solvents A and B respectively to a 3:97 mixtureof solvents A and B. The reported molecular ion corresponds to the[M+H]+ unless otherwise specified; for molecules with multiple isotopicpatterns (Br, Cl, etc.) the reported value is the one obtained for thelowest isotope mass unless otherwise specified;

(ix) ion exchange purification was generally performed using an SCX-2(Biotage) cartridge;

(x) where reactions refer to the use of a microwave, one of thefollowing microwave reactors were used: Biotage Initiator, PersonalChemistry Emrys Optimizer, Personal Chemistry Smithcreator or CEMExplorer;

(xi) intermediate purity was assessed by thin layer chromatographic,mass spectroscopy. LCMS. UPLC/MS. HPLC and/or NMR analysis;

(xii) the following abbreviations have been used:

-   -   BEH ethylene bridged hybrid    -   BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium        hexafluorophosphate    -   DBU 1,8-diazabicyclo(5.4.0)undec-7-ene    -   DCM dichloromethane    -   DEA diethylamine    -   DIPEA diisopropylethylamine    -   DMF N,N-dimethylformamide    -   DMF-DMA N,N-dimethylformamide dimethyl acetal    -   DMSO dimethylsulfoxide    -   e.e. enantiomeric excess    -   HATU        (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid hexafluorophosphate)    -   HCl hydrochloric acid    -   HPLC high performance liquid chromatography    -   MS mass spectrometry    -   NMR nuclear magnetic resonance    -   PAT process analytical technology    -   PyAOP ((7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium        hexafluorophosphate)    -   PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium        hexafluorophosphate)    -   TBME/MTBE tert-butyl methyl ether    -   TEA triethylamine    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   tR retention time    -   PTSA p-toluenesulfonic acid    -   UPLC ultra performance liquid chromatography

(xiii) XRPD: Analytical Instrument: Bruker D4

The X-ray powder diffractogram was determined by mounting a sample ofthe crystalline material on a Bruker (Bruker D4) single silicon crystal(SSC) wafer mount and spreading out the sample into a thin layer withthe aid of a microscope slide. The sample was spun at 30 revolutions perminute (to improve counting statistics) and irradiated with X-raysgenerated by a copper long-fine focus tube operated at 40 kV and 40 mAwith a wavelength of 1.5418 angstroms. The collimated X-ray source waspassed through an automatic variable divergence slit set at V20 and thereflected radiation directed through a 5.89 mm anti scatter slit and a9.55 mm detector slit. Samples were measured in reflection geometry inθ-2θ configuration over the scan range 2° to 40° 20 with a nominal 0.12second exposure per 0.02° increment. The instrument was equipped with aPosition sensitive detector (Lynxeye). Persons skilled in the art ofX-ray powder diffraction will understand that the relative intensity ofpeaks can be affected by, for example, grains above 30 microns in sizeand non-unitary aspect ratios that may affect analysis of samples. Theskilled person will also understand that the position of reflections canbe affected by the precise height at which the sample sits in thediffractometer and the zero calibration of the diffractometer. Thesurface planarity of the sample may also have a small effect. Hence thediffraction pattern data presented are not to be taken as absolutevalues;

(xiv) Differential Scanning Calorimetry: Analytical Instrument: TAInstruments Q2000 DSC

Typically less than 3 mg of material contained in a standard aluminiumpan fitted with a lid was heated over the temperature range 25° C. to300° C. at a constant heating rate of 10° C. per minute. A purge gasusing nitrogen was used—flow rate 50 ml per minute. Thermal data wasanalyzed using standard software, e.g., Universal v.4.5A from TAINSTRUMENTS®;

(xv) For the Thermogravimetry Analysis (TGA) the instrument used was TAInstruments Q5000 TGA

Typically less than 5 mg was placed into an aluminum sample pan andtransferred to the TGA furnace. The instrument was purged with nitrogenat 50 mL/min and data collected between 25° C. and just below themelting point of the compound, using a constant heating rate of 10°C./minute. Thermal data was analyzed using standard software, e.g.,Universal v.4.5A from TA INSTRUMENTS®.

Example 1N-(4-[(5,7-dimethoxyquinazolin-4-yl)amino]-3-fluorophenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide

4-Chloro-5,7-dimethoxyquinazoline (78 mg, 0.4 mmol) was added toN-(4-amino-3-fluorophenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide(80 mg, 0.3 mmol) in isopropanol (2.5 mL) under nitrogen. The resultingmixture was stirred at 80° C. for 4 hours. The reaction mixture wasdiluted with water. The precipitate was collected by filtration, washedwith water (10 mL) and dried under vacuum to afford crude product as apurple solid. The crude product was purified by preparative HPLC.Fractions containing the desired compound were evaporated to dryness toafford the title compound as a beige solid (80 mg, 58%). 1H NMR (400MHz, DMSO-d6) δ 1.25 (6H, d), 2.95-3.06 (1H, m), 3.91 (3H, s), 4.06 (3H,s), 5.29 (2H, s), 6.72 (1H, d), 6.80 (1H, d), 7.28-7.36 (1H, m),7.67-7.75 (1H, m), 7.88 (1H, s), 8.19 (1H, t), 8.41 (1H, s), 9.81 (1H,s), 10.71 (1H, s); m/z (ES+), [M+H]+=466; acid, HPLC tR=1.53 min.

The intermediates used in Example 1 were prepared as follows:

Preparation of 2-Fluorobenzene-1,4-diamine

Zinc powder (4.2 g, 64.1 mmol) was added to ammonium chloride (3.4 g,64.1 mmol), 3-fluoro-4-nitroaniline (500 mg, 3.2 mmol) and water (4 mL)in ethanol (15 mL) under nitrogen. The resulting mixture was stirred at25° C. for 2 hours. The mixture was filtered, and the filtrate wasevaporated to dryness to give a crude residue which was purified byflash silica chromatography, elution gradient 1 to 10% methanol in DCM(0.1% DIPEA). Pure fractions were evaporated to dryness to afford thetitle compound as a black oil (405 mg, 100%). 1H NMR (DMSO-d6, 300 MHz)δ 6.27 (1H, dd), 6.39 (1H, dd), 6.58 (1H, dd), 9.74 (2H, s); m/z (ES+),[M+H]+=127; acid. HPLC tR=0.227 min.

Preparation of Ethyl 2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetate

A 30% solution of ethyl 2-azidoacetate in DCM (19.5 g, 45.4 mmol) wasadded as a solution in acetonitrile (27 mL) over 5 minutes to asuspension of copper(I) iodide (0.17 g, 0.9 mmol), 3-methylbut-1-yne(5.1 mL, 49.9 mmol) and triethylamine (0.13 mL, 0.9 mmol) inacetonitrile (27 mL) at room temperature. The mixture was stirred for 3days at room temperature. The mixture was concentrated and the residuewas partitioned between water (150 mL) and ethyl acetate (150 mL). Theaqueous layer was extracted with ethyl acetate (100 mL) and the extractscombined with the organic layer. The combined extracts were dried andevaporated to dryness. The crude product was purified by flash silicachromatography, elution gradient 30 to 50% ethyl acetate in heptane.Pure fractions were evaporated to dryness to afford the title compoundas a white crystalline solid (8.06 g, 90%). 1H NMR (500 MHz, DMSO, 27°C.) δ 1.21 (3H, t), 1.22 (6H, d), 2.98 (1H, hept), 4.16 (2H, q), 5.30(2H, s), 7.82 (1H, d); m/z: ES+ [M+H]+ 198.

Preparation of 2-(4-Isopropyl-1H-1,2,3-triazol-1-yl)acetic acid

Lithium hydroxide hydrate (10.2 g, 242.5 mmol) was added as a solutionin water (540 mL) to ethyl 2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetate(15.9 g, 80.8 mmol) in THF (180 mL). The mixture was stirred for 90minutes, then concentrated. The resulting aqueous solution was acidifiedto pH 5 with 2M HCl and extracted with ethyl acetate (200 mL). Theaqueous layer was evaporated to dryness to afford the title compound asa white solid containing LiCl (28.2 g, 100%, 48% strength), which wasused without further purification. 1H NMR (500 MHz, DMSO, 27° C.) δ 1.20(6H, d), 2.92 (1H, hept), 4.59 (2H, s), 7.62 (1H, d); m/z: ES+[M+H]+170.

Preparation ofN-(4-Amino-3-fluorophenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide

HATU (678 mg, 1.8 mmol) was added to2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetic acid (201 mg, 1.2 mmol),2-fluorobenzene-1,4-diamine (150 mg, 1.2 mmol) and DIPEA (0.3 mL, 1.8mmol) in DMF (7 mL) under nitrogen. The resulting mixture was stirred at25° C. for 6 hours, then evaporated to dryness. The crude product waspurified by preparative HPLC. Fractions containing the desired compoundwere evaporated to dryness to afford the title compound as a black solid(200 mg, 61%). 1H NMR (DMSO-d6, 400 MHz) δ 1.24 (6H, d), 2.99 (1H, dt),4.98 (2H, s), 5.18 (2H, s), 6.72 (1H, dd), 6.99 (1H, dd), 7.38 (1H, dd),7.85 (1H, s), 10.25 (1H, s); m/z (ES+), [M+H]+=278; acid, HPLC tR=0.979min.

Example 2N-{4-[(5-fluoro-6,7-dimethoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide

HATU (84 mg, 0.2 mmol) was added portionwise toN1-(5-fluoro-6,7-dimethoxyquinazolin-4-yl)benzene-1,4-diamine (100 mg,0.2 mmol), 2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetic acid (52 mg, 0.2mmol) and DIPEA (0.06 mL, 0.4 mmol) in DMF (1 mL) at 25° C. undernitrogen. The resulting solution was stirred at room temperature for 1hour. The reaction mixture was concentrated and diluted with DCM (100mL), and washed sequentially with 0.1M HCl (20 mL), water (10 mL), andsaturated Na₂CO₃ (20 mL). The organic layer was dried, filtered andevaporated to dryness. The crude product was purified by preparativeHPLC. Fractions containing the desired compound were evaporated todryness to afford the title compound as a white solid (60 mg, 70%). 1HNMR (400 MHz, DMSO-d6) δ 1.26 (6H, d), 2.94-3.07 (1H, m), 3.91 (3H, s),4.00 (3H, s), 5.27 (2H, s), 7.15 (1H, d), 7.59 (2H, d), 7.69 (2H, d),7.88 (1H, d), 8.45 (1H, s), 8.94 (1H, d), 10.48 (1H, s); m/z (ES+),[M+H]+=466; acid, HPLC tR=1.38 min.

The intermediates used in Example 2 were prepared as follows:

Preparation of 2-Fluoro-3,4-dimethoxybenzaldehyde

Titanium(IV)chloride (8 g, 42.3 mmol) in DCM (12 mL) was added dropwiseto 1-fluoro-2,3-dimethoxybenzene (4 g, 25.6 mmol) in DCM (40 mL) at 0°C. over a period of 15 minutes under nitrogen. This was followed by theaddition of dichloro(methoxy)methane (3.2 g, 28.2 mmol) in anhydrous DCM(8 mL) dropwise over 12 minutes. The resulting solution was stirred at0° C. for 30 minutes, then stirred at room temperature for 5 hours. Thereaction mixture was quenched with water (200 mL), extracted with DCM(2×100 mL), the organic layer was dried, filtered and evaporated todryness. The crude product was purified by flash silica chromatography,elution gradient 0 to 2% methanol in DCM. Pure fractions were evaporatedto dryness to afford the title compound (4.6 g, 98%) as a yellow solid.1H NMR (DMSO-d6, 300 MHz) δ 3.84 (3H, d), 3.95 (3H, s), 7.11 (1H, p),7.61 (1H, p), 10.06 (1H, s); m/z (ES+), [M+H]+=185; acid, HPLC tR=1.434min.

Preparation of 2-Fluoro-3,4-dimethoxy-6-nitrobenzaldehyde

Potassium nitrate (2.8 g, 27.4 mmol) was added portionwise to2-fluoro-3,4-dimethoxybenzaldehde (4.2 g, 22.8 mmol) and concentratedsulfuric acid (30 ml, 562.9 mmol) at 0° C. The resulting solution wasstirred at room temperature for 3 hours. The reaction mixture was pouredinto ice water. The precipitate was collected by filtration, washed withice water (75 mL) and dried under vacuum to afford the title compound asa brown solid (3.2 g, 61%). 1H NMR (DMSO-d6, 300 MHz) δ 3.95 (3H, d),4.02 (3H, s), 7.71 (1H, d), 10.08 (1H, s); m/z (ES+), [M+H]+=230; acid,HPLC tR=1.206 min.

Preparation of 2-Fluoro-3,4-dimethoxy-6-nitrobenzoic acid

Sodium perborate (4.3 g, 27.9 mmol) was added portionwise to2-fluoro-3,4-dimethoxy-6-nitrobenzaldehyde (3.2 g, 14 mmol) in aceticacid (45 mL) over a period of 2 minutes. The resulting mixture wasstirred at 50° C. for 3 days. The reaction mixture was evaporated todryness and dissolved in DCM (200 mL), and washed sequentially withwater (2×100 mL). The aqueous layer was separated, frozen andlyophilized to afford the title compound as yellow solid (2.9 g, 85%).1H NMR (DMSO-d6, 300 MHz) δ 3.89 (6H, d), 7.41 (1H, d); m/z (ES+),[M+H]+=not found; acid. HPLC tR=1.041 min.

Preparation of 2-Fluoro-3,4-dimethoxy-6-nitrobenzamide

SOCl₂ (100 mL, 1370 mmol) was added portionwise to2-fluoro-3,4-dimethoxy-6-nitrobenzoic acid (2.9 g, 11.8 mmol). Theresulting mixture was stirred at 90° C. for 2 hours. The solvent wasremoved under reduced pressure and the resulting residue was dissolvedin THF (30 mL). The solvent was cooled to 0° C. and ammonia (0.5M inTHF) (47.3 mL, 23.7 mmol) was added slowly. The resulting solution wasstirred at room temperature for 2 hours. The reaction mixture wasevaporated to dryness and dissolved in DCM (200 mL), and washedsequentially with saturated NaHCO₃ (2×50 mL) and water (2×50 mL). Theorganic layer was dried, filtered and evaporated to dryness. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 6% methanol in DCM. Pure fractions were evaporated to dryness toafford the title compound as a brown solid (0.6 g, 21%). 1H NMR(DMSO-d6, 300 MHz) δ 3.98 (6H, d), 7.69 (1H, d).

Preparation of 6-Amino-2-fluoro-3,4-dimethoxybenzamide

Iron (412 mg, 7.4 mmol) was added portionwise to2-fluoro-3,4-dimethoxy-6-nitrobenzamide (600 mg, 2.5 mmol) in aceticacid (3 mL). The resulting mixture was stirred at 105° C. for 15minutes. The reaction mixture was evaporated to dryness and dissolved inDCM (100 mL), and washed sequentially with water (2×50 mL). The organiclayer was dried, filtered and evaporated to afford the title compound asa yellow oil (500 mg, 95%), which was used without further purification.m/z (ES+), [M+H]+=215; acid, HPLC tR=0.964 min.

Preparation of 5-Fluoro-6,7-dimethoxyquinazolin-4(3H)-one

PTSA (35.5 mg, 0.2 mmol) was added to6-amino-2-fluoro-3,4-dimethoxybenzamide (200 mg, 0.9 mmol) andtrimethoxymethane (5 mL) at 25° C. under nitrogen. The resultingsuspension was stirred at 100° C. for 3 hours. The reaction was cooledto room temperature. The precipitate was collected by filtration, washedwith ethyl acetate (5 mL) and evaporated to dryness to afford the titlecompound as a beige solid (140 mg, 67%), which was used without furtherpurification. 1H NMR (400 MHz. DMSO-d6) δ 3.83 (3H, s), 3.95 (3H, s),7.01-7.08 (1H, m), 8.00 (1H, d), 12.12 (1H, s); m/z (ES+), [M+H]+=225;acid, HPLC tR=0.87 min.

Preparation ofN1-(5-Fluoro-6,7-dimethoxyquinazolin-4-yl)benzene-1,4-diamine

PyAOP (393 mg, 0.8 mmol) was added to5-fluoro-6,7-dimethoxyquinazolin-4(3H)-one (130 mg, 0.6 mmol) and DBU(0.22 mL, 1.5 mmol) in acetonitrile (4 mL) at 25° C. under nitrogen. Theresulting solution was stirred at room temperature for 10 minutes.Benzene-1,4-diamine (94 mg, 0.9 mmol) was added to this at 25° C. undernitrogen. The resulting solution was stirred at room temperature for 3hours. The reaction mixture was quenched with water (20 mL), extractedwith DCM (2×25 mL), the organic layer was dried, filtered and evaporatedto afford a dark oil which solidified on standing. The crude product waspurified by flash silica chromatography, elution gradient 0 to 2%methanol in DCM. Pure fractions were evaporated to dryness to afford thetitle compound as a yellow solid (220 mg.>100%). 1H NMR (400 MHz,DMSO-d6) δ 3.89 (3H, s), 3.98 (3H, s), 5.05 (2H, s), 6.57 (2H, d), 7.09(1H, s), 7.26 (2H, d), 8.34 (1H, s), 8.65 (1H, d); m/z (ES+),[M+H]+=315; acid, HPLC tR=0.87 min.

Example 3 and Example 4(R)—N-(4-{[5-Ethoxy-7-(tetrahydrofuran-3-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamideand(S)—N-(4-{[5-Ethoxy-7-(tetrahydrofuran-3-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide

Potassium tert-butoxide (150 mg, 1.3 mmol) was added totetrahydrofuran-3-ol (78 mg, 0.9 mmol) andN-(4-((5-ethoxy-7-fluoroquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide(200 mg, 0.4 mmol) in DMF (4 mL) at 25° C. under air. The resultingmixture was stirred at 80° C. for 5 hours. The crude product waspurified by preparative HPLC. Fractions containing the desired compoundwere evaporated to dryness to afford the racemic title compound as awhite solid (160 mg, 70%); m/z (ES+), [M+H]+=518; TFA, HPLC tR=1.443min. This compound was purified by preparative chiral-HPLC on aChiralpak IA column, eluting isocratically with 30% ethanol in MTBE(0.1% DEA) as eluent. The fractions containing the desired compound wereevaporated to dryness to afford one enantiomer ofN-(4-((5-ethoxy-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamideas a white solid (68 mg, 43%). 1H NMR (400 MHz, DMSO, 20° C.) δ 1.25(6H, d), 1.56 (3H, t), 1.99-2.06 (1H, m), 2.25-2.35 (1H, m), 2.95-3.02(1H, m), 3.75-3.95 (4H, m), 4.32 (2H, t), 5.22 (1H, t), 5.27 (2H, s),6.68 (1H, s), 6.76 (1H, s), 7.60 (2H, d), 7.78 (2H, d), 7.88 (1H, s),8.46 (1H, s), 9.98 (1H, s), 10.50 (1H, s); m/z (ES+), [M+H]+=518; TFA,HPLC tR=1.463 min. This was then followed by the other enantiomer ofN-(4-((5-ethoxy-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamideas a white solid (62 mg, 39%). 1H NMR (400 MHz, DMSO, 20° C.) δ 1.25(6H, d), 1.56 (3H, t), 1.98-2.05 (1H, m), 2.25-2.35 (1H, m), 2.95-3.02(1H, m), 3.75-3.95 (4H, m), 4.32 (2H, t), 5.22 (1H, t), 5.27 (2H, s),6.68 (1H, s), 6.76 (1H, s), 7.60 (2H, d), 7.78 (2H, d), 7.88 (1H, s),8.46 (1H, s), 9.99 (1H, s), 10.50 (1H, s); m/z (ES+), [M+H]+=518; TFA,HPLC tR=1.470 min.

The intermediates used in Example 3 and Example 4 were prepared asfollows:

Preparation of 5-Ethoxy-7-fluoroquinazolin-4(3H)-one

Sodium ethanolate (7.5 g, 109.8 mmol) was added to5,7-difluoroquinazolin-4(3H)-one (4 g, 22 mmol) in DMSO (20 mL) cooledat 0° C. under nitrogen. The resulting solution was stirred at roomtemperature for 2 hours. The reaction mixture was diluted with water(200 mL) and adjusted to pH 7 with 2M HCl. The resulting solid wasisolated by filtration to afford the title compound as yellow solid (4.4g, 96%). 1H NMR (300 MHz, DMSO, 21° C.) δ 1.37 (3H, t), 4.09-4.16 (2H,m), 6.88-6.94 (2H, m), 7.98 (1H, s), 11.98 (1H, s); m/z (ES+),[M+H]+=209; TFA, HPLC tR=0.988 min.

Preparation of N1-(5-Ethoxy-7-fluoroquinazolin-4-yl)benzene-1,4-diamine

BOP (8.9 g, 20.2 mmol) was added to5-ethoxy-7-fluoroquinazolin-4(3H)-one (3 g, 14.4 mmol) and DBU (4.3 mL,28.8 mmol) in acetonitrile (20 mL) at 25° C. under nitrogen. Theresulting solution was stirred at 60° C. for 3 hours.Benzene-1,4-diamine (2.2 g, 20.2 mmol) was added to this at 25° C. undernitrogen. The resulting solution was stirred at 60° C. for 3 hours. Thesolvent was removed under reduced pressure. The reaction mixture wasquenched with water (10 mL), extracted with DCM (3×25 mL), the organiclayer was dried, filtered and evaporated to afford a dark oil. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 4% methanol in DCM. Pure fractions were evaporated to dryness toafford the title compound as a yellow solid (2.6 g, 599%). 1H NMR (300MHz, DMSO, 23° C.) δ 1.68 (3H, t), 4.27-4.29 (2H, m), 6.65 (1H, s),6.74-6.77 (2H, m), 7.06 (1H, d), 7.45-7.48 (2H, m), 8.54 (1H, d), 9.69(1H, s); m/z (ES+), [M+H]+=299; TFA, HPLC tR=0.871 min.

Preparation ofN-(4-((5-Ethoxy-7-fluoroquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide

HATU (4.7 g, 12.3 mmol) was added toN1-(5-ethoxy-7-fluoroquinazolin-4-yl)benzene-1,4-diamine (2.5 g, 8.2mmol), 2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetic acid (2.1 g, 12.3mmol) and DIPEA (4.3 mL, 24.6 mmol) in DMF (10 mL) at 25° C. under air.The resulting mixture was stirred at room temperature for 2 hours. Thereaction mixture was diluted with ethyl acetate (150 mL), and washedsequentially with water (2×150 mL) and saturated brine (75 mL). Theorganic layer was dried, filtered and evaporated to dryness. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 4% methanol in DCM. Pure fractions were evaporated to dryness toafford the title compound as a yellow solid (1.5 g, 41%). 1H NMR (300MHz, DMSO, 23° C.) δ 1.25 (6H, d), 1.58 (3H, t), 2.95-3.05 (1H, m),4.35-4.42 (2H, m), 5.26 (2H, s), 7.05-7.12 (2H, m), 7.60-7.63 (2H, m),7.77-7.80 (2H, m), 7.87 (1H, s), 8.50 (1H, s), 10.03 (1H, s), 10.51 (1H,s); m/z (ES+), [M+H]+=450; TFA, HPLC tR=1.048 min.

Example 5N-(4-((5-Ethoxy-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide

Potassium tert-butoxide (112 mg, 1 mmol) was added toN-(4-((5-ethoxy-7-fluoroquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide(150 mg, 0.3 mmol) and tetrahydro-4H-pyran-4-ol (102 mg, 1 mmol) in DMF(2 mL) at room temperature. The resulting solution was stirred at 80° C.for 7 hours. The crude product was purified by preparative HPLC.Fractions containing the desired compound were evaporated to dryness toafford the title compound (75 mg, 42%) as a white solid. 1H NMR(DMSO-d6, 400 MHz) δ 1.26 (6H, d), 1.58 (3H, t), 1.65 (2H, t), 2.01-2.11(2H, m), 2.95-3.07 (1H, m), 3.52-3.58 (2H, m), 3.86-3.91 (2H, m), 4.35(2H, q), 4.80-4.86 (1H, m), 5.27 (2H, s), 6.70 (1H, d), 6.88 (1H, d),7.57-7.65 (2H, m), 7.75-7.84 (2H, m), 7.89 (1H, d), 8.44 (1H, s), 9.98(1H, s), 10.50 (1H, s); m/z (ES+), [M+H]+=532; acid, HPLC tR=1.485 min.

Example 6N-(4-((7-(2-(Dimethylamino)ethoxy)-5-ethoxyquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide

Potassium tert-butoxide (75 mg, 0.7 mmol) was added to2-(dimethylamino)ethan-1-ol (39.7 mg, 0.4 mmol) andN-(4-((5-ethoxy-7-fluoroquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide(100 mg, 0.2 mmol) in DMF (2 mL) at 25° C. under air. The resultingmixture was stirred at 80° C. for 15 hours. The crude product waspurified by preparative HPLC. Fractions containing the desired compoundwere evaporated to dryness to afford the title compound as a lightyellow solid (51 mg, 44%). 1H NMR (400 MHz DMSO, 20° C.) δ 1.26 (6H, d),1.58 (3H, t), 2.25 (6H, s), 2.65-2.69 (2H, t), 2.95-3.05 (1H, m), 4.19(2H, t), 4.31-4.36 (2H, m), 5.27 (2H, s), 6.90 (1H, s), 6.80 (1H, s),7.61 (2H, d), 7.78 (2H, d), 7.88 (1H, s), 8.45 (1H, s), 9.97 (1H, s),10.50 (1H, s); m/z (ES+), [M+H]+=519; TFA, HPLC tR=1.193 min.

Example 7N-(4-((5-Ethoxy-7-methoxyquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide

Sodium methoxide (24 mg, 0.4 mmol) was added to methanol (43 mg, 1.3mmol) andN-(4-((5-ethoxy-7-fluoroquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide(100 mg, 0.2 mmol) in DMF (2 mL) at 25° C. under air. The resultingmixture was stirred at room temperature for 5 hours. The crude productwas purified by preparative HPLC. Fractions containing the desiredcompound were evaporated to dryness to afford the title compound as awhite solid (70 mg, 68%). 1H NMR (400 MHz, DMSO, 20° C.) δ 1.26 (6H, d),1.58 (3H, t), 2.95-3.05 (1H, m), 3.90 (3H, s), 4.31-4.36 (2H, m), 5.27(2H, s), 6.70 (1H, s), 6.79 (1H, s), 7.61 (2H, d), 7.79 (2H, d), 7.88(1H, s), 8.46 (1H, s), 9.97 (1H, s), 10.50 (1H, s). m/z (ES+),[M+H]+=462; TFA, HPLC tR=1.445 min.

Example 8N-(4-((5-Ethoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide

2-Methoxyethan-1-ol (34 mg, 0.4 mmol) was added toN-(4-((5-ethoxy-7-fluoroquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide(100 mg, 0.2 mmol) and potassium tert-butoxide (75 mg, 0.7 mmol) in DMF(2 mL) at 25° C. under air. The resulting mixture was stirred at 80° C.for 5 hours. The crude product was purified by preparative HPLC.Fractions containing the desired compound were evaporated to dryness toafford the title compound as a white solid (63 mg, 56%). 1H NMR (400MHz, DMSO, 20° C.) δ 1.26 (6H, d), 1.58 (3H, t), 2.95-3.05 (1H, m), 3.34(3H, s), 3.71 (2H, t), 4.25 (2H, t), 4.31-4.36 (2H, m), 5.27 (2H, s),6.72 (1H, s), 6.79 (1H, s), 7.61 (2H, d), 7.78 (2H, d), 7.88 (1H, s),8.45 (1H, s), 9.97 (1H, s), 10.50 (1H, s); m/z (ES+), [M+H]+=506; TFA,HPLC tR=1.445 min.

Example 9N-(4-((5-Ethoxy-7-(oxetan-3-yloxy)quinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide

Potassium tert-butoxide (50 mg, 0.4 mmol) was added to oxetan-3-ol (33mg, 0.4 mmol) andN-(4-((5-ethoxy-7-fluoroquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide(100 mg, 0.2 mmol) in DMF (2 mL) at 25° C. under air. The resultingmixture was stirred at 80° C. for 5 hours. The crude product waspurified by preparative HPLC. Fractions containing the desired compoundwere evaporated to dryness to afford the title compound as a white solid(68 mg, 61%). 1H NMR (400 MHz, DMSO, 20° C.) δ 1.26 (6H, d), 1.58 (3H,t), 2.98-3.05 (1H, m), 4.33-4.38 (2H, m), 4.60 (2H, t), 5.00 (2H, t),5.27 (2H, s), 5.45-5.50 (1H, m), 6.46 (1H, s), 6.72 (1H, s), 7.61 (2H,d), 7.78 (2H, d), 7.88 (1H, s), 8.45 (1H, s), 9.97 (1H, s), 10.50 (1H,s); m/z (ES+), [M+H]+=504; TFA, HPLC tR=1.883 min.

Example 10N-(4-{[5-Methoxy-7-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide

Potassium tert-butoxide (85 mg, 0.8 mmol) was added toN-(4-((7-fluoro-5-methoxyquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide(110 mg, 0.3 mmol) and tetrahydro-4H-pyran-4-ol (77 mg, 0.8 mmol) in DMF(3 mL) at room temperature. The resulting solution was stirred at 80° C.for 7 hours. The crude product was purified by preparative HPLC.Fractions containing the desired compound were evaporated to dryness toafford the title compound as a white solid (38 mg, 29%). 1H NMR(DMSO-d6, 400 MHz) δ 1.26 (6H, d), 1.60-1.69 (2H, m), 2.05 (2H, d),2.95-3.10 (1H, m), 3.56 (2H, t), 3.89 (2H, t), 4.09 (3H, s), 4.81-4.85(1H, m), 5.27 (2H, s), 6.69 (1H, d), 6.87 (1H, d), 7.57-7.66 (2H, m),7.74-7.84 (2H, m), 7.89 (1H, d), 8.40 (1H, s), 9.78 (1H, s), 10.52 (1H,d); m/z (ES+), [M+H]+=518; TFA, HPLC tR=8.32 min.

The intermediates used in Example 10 were prepared as follows:

Preparation of 7-Fluoro-5-methoxyquinazolin-4(3H)-one

Sodium methoxide (in methanol) (9.9 g, 54.9 mmol) was added to5,7-difluoroquinazolin-4(3H)-one (2 g, 11 mmol) in DMSO (10 mL) cooledto 0° C. under nitrogen. The resulting solution was stirred at roomtemperature for 2 hours. The reaction mixture was diluted with waterthen neutralised with 2M HCl. The resulting precipitate was collected byfiltration, washed with water (20 mL) and dried under vacuum to affordthe title compound as a white solid (1.9 g, 89%), which was used withoutfurther purification. 1H NMR (300 MHz, DMSO-d6) δ 3.87 (3H, s),6.87-7.03 (2H, m), 8.00 (1H, s), 12.04 (1H, s); m/z (ES+), [M+H]+=195;acid, HPLC tR=0.90 min.

Preparation of N1-(7-Fluoro-5-methoxyquinazolin-4-yl)benzene-1,4-diamine

BOP (3.2 g, 7.2 mmol) was added to7-fluoro-5-methoxyquinazolin-4(3H)-one (1 g, 5.2 mmol) and DBU (1.6 mL,10.3 mmol) in acetonitrile (20 mL) at 25° C. under nitrogen. Theresulting solution was stirred at 60° C. for 15 minutes.Benzene-1,4-diamine (0.8 g, 7.2 mmol) was added to this at 25° C. undernitrogen. The resulting solution was stirred at 60° C. for 1 hour. Thesolvent was removed under reduced pressure. The reaction mixture wasquenched with water (10 mL), extracted with DCM (3×25 mL), the organiclayer was dried, filtered and evaporated to afford a dark oil. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 4% methanol in DCM. Pure fractions were evaporated to dryness toafford the title compound as a yellow solid (2.1 g, >100%). 1H NMR (400MHz, DMSO-d6) δ 4.10 (3H, s), 5.12 (2H, s), 6.59 (2H, d), 6.97-7.07 (2H,m), 7.31 (2H, d), 8.34 (1H, s), 9.59 (1H, s); m/z (ES+), [M+H]+=285;acid, HPLC tR=0.81 min.

Preparation ofN-(4-((7-Fluoro-5-methoxyquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide

HATU (1.9 g, 4.9 mmol) was added portionwise toN1-(7-fluoro-5-methoxyquinazolin-4-yl)benzene-1,4-diamine (2.1 g, 4.4mmol), 2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetic acid (1.2 g, 4.9mmol) and DIPEA (1.70 mL, 9.8 mmol) in acetonitrile (100 mL) at 25° C.under nitrogen. The resulting solution was stirred at room temperaturefor 1 hour. The solvent was removed under reduced pressure. The reactionmixture was diluted with water. The precipitate was collected byfiltration, washed with water/acetonitrile (50 mL, 5:1) and dried undervacuum to afford the title compound as a pale yellow solid (1.2 g, 62%),which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ1.25 (6H, d), 2.95-3.05 (1H, m), 4.13 (3H, s), 5.27 (2H, s), 7.01-7.14(2H, m), 7.61 (2H, d), 7.75 (2H, d), 7.88 (1H, d), 8.46 (1H, s), 9.87(1H, s), 10.51 (1H, s); m/z (ES+), [M+H]+=436; base, HPLC tR=0.82 min.

Example 112-[4-(Propan-2-yl)-1H-1,2,3-triazol-1-yl]-N-{4-[(5,6,7-trimethoxyquinazolin-4-yl)amino]phenyl}acetamide

HATU (64 mg, 0.2 mmol) added to suspension of2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetic acid (42 mg, 0.1 mmol),N1-(5,6,7-trimethoxyquinazolin-4-yl)benzene-1,4-diamine (44 mg, 0.1mmol) and N-ethyl-N-isopropylpropan-2-amine (0.05 mL, 0.3 mmol) in DMF(5 mL). The reaction was stirred at ambient temperature for 16 hours.The reaction mixture was quenched with water (10 mL), diluted with ethylacetate (10 mL) and the layers were separated. The aqueous layer waswashed with ethyl acetate (3×10 mL) and the organic layers werecombined, washed with brine (10 mL), dried, filtered and concentrated invacuo. The crude product was purified by preparative HPLC. Fractionscontaining the desired compound were evaporated to dryness to afford thetitle compound as a white solid (41 mg, 76%). 1H NMR (500 MHz, DMSO, 27°C.) δ 1.24 (3H, s), 1.25 (3H, s), 2.99 (1H, pd), 3.86 (3H, s), 3.95 (3H,s), 4.12 (3H, s), 5.25 (2H, s), 7.06 (1H, s), 7.59 (2H, d), 7.82 (2H,d), 7.86 (1H, d), 8.43 (1H, s), 9.88 (1H, s), 10.45 (1H, s); m/z: ES+[M+H]+ 478.

The intermediates used in Example 11 were prepared as follows:

Preparation of 5,6,7-Trimethoxyquinazolin-4(3H)-one

A solution of ethyl 6-amino-2,3,4-trimethoxybenzoate hydrochloride (200mg, 0.7 mmol) and formimidamide acetate (214 mg, 2.1 mmol) were heatedin 2-methoxyethanol (5 mL) at 125° C. for 2 hours. The mixture wascooled to ambient temperature and evaporated. The residue was treatedwith water (10 mL). The resulting precipitate was collected byfiltration, washed with water and dried under vacuum to afford the titlecompound as a brown solid (164 mg, 100%), which was used without furtherpurification. 1H NMR (500 MHz, CDCl₃, 27° C.) δ 3.95 (3H, s), 3.99 (2H,s), 4.02 (3H, s), 7.01 (1H, s), 7.99 (1H, s), 11.02 (1H, s). m/z: ES+[M+H]+ 237.

Preparation of N1-(5,6,7-Trimethoxyquinazolin-4-yl)benzene-1,4-diamine

DBU (0.2 mL, 1.4 mmol) was added to a mixture of5,6,7-trimethoxyquinazolin-4(3H)-one (130 mg, 0.6 mmol) and PyBOP (372mg, 0.7 mmol) in acetonitrile (10 mL) and was heated at 60° C. for 1hour. Benzene-1,4-diamine (119 mg, 1.1 mmol) was added and stirring at60° C. was continued for a further 2 hours. The reaction mixture wascooled to room temperature and concentrated in vacuo. The crude mixturewas dissolved in acetone and 2 mL of 2M HCl in diethyl ether was addedto form a precipitate. The precipitate was filtered and washed withacetone, then dissolved in a saturated aqueous solution of sodiumhydrogen carbonate (20 mL) and ethyl acetate (20 mL). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (3×20mL). The combined organic layers were dried, filtered and concentratedin vacuo to afford the title compound as a beige solid (73 mg, 41%),which was used without further purification. m/z: ES+ [M+H]+ 327.

Example 12N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide

A mixture ofN-(4-aminophenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide (5.4 g,20.7 mmol) and(E)-N′-(2-cyano-3-fluoro-5-(2-methoxyethoxy)phenyl)-N,N-dimethylformimidamide(5.2 g, 19.7 mmol) in acetic acid (12 mL) was stirred at 60° C. for 35minutes. The mixture was poured into water (150 mL), the mixture wasstirred and sonicated. The resulting precipitate was collected byfiltration, washed with water and dried. The solid was dissolved inDCM/methanol (12:1, 600 mL) and the solution washed with 0.2M NaHCO₃solution (600 mL). The aqueous layer was extracted with DCM/methanol(12:1, 2×200 mL) and the extracts combined with the organic layer. Thecombined organic extracts were dried, filtered and evaporated to give abeige solid. The crude product was crystallised from hot ethanol (700mL). After cooling to ambient temperature and stirring for 2 hours, thecrystalline solid was collected by filtration, washed with cold ethanoland dried under high vacuum at 50° C. to afford 7.4 g of crude product.The crude product was further purified by recrystallisation in hotethanol (800 ml). After cooling to ambient temperature and stirring for20 hours, the crystalline solid was collected by filtration; the solidswere collected and dried under vacuum at 50° C. for 72 hours to give thetitle compound as a white crystalline solid (6.2 g, 58%). 1H NMR (500MHz, DMSO, 27° C.) δ 1.24 (6H, d), 2.99 (1H, pd), 3.32 (3H, s),3.67-3.73 (2H, m), 4.24-4.3 (2H, m), 5.26 (2H, s), 7.04 (1H, d), 7.13(1H, dd), 7.53-7.61 (2H, m), 7.63-7.69 (2H, m), 7.86 (1H, d), 8.44 (1H,s), 8.95 (1H, d), 10.47 (1H, s); m/z: ES+ [M+H]+ 480.

The intermediates used in Example 12 were prepared as follows:

Preparation of Tert-Butyl(4-(2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamido)phenyl)carbamate

HATU (18.4 g, 48.3 mmol) was added to a solution of tert-butyl(4-aminophenyl)carbamate (8.4 g, 40.3 mmol),2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetic acid (19.4 g, 44.3 mmol) andDIPEA (10.5 mL, 60.4 mmol) at ambient temperature. The mixture wasstirred at ambient temperature for 16 hours. The mixture wasconcentrated to 75 mL volume, diluted with water (700 mL) and extractedwith ethyl acetate (3×300 mL). The combined ethyl acetate extracts werewashed with 0.5M citric acid solution (300 mL), water (4×300 mL), 0.5MNaHCO₃ solution (200 mL), water (200 mL), brine (200 mL) and dried. Thesolution was evaporated to dryness and the residue was recrystallisedfrom acetonitrile to afford the title compound as a white solid (8.2 g,57%). 1H NMR (500 MHz, DMSO, 27° C.) δ 1.23 (6H, d), 1.45 (9H, s), 2.98(1H, hept), 5.20 (2H, s), 7.38 (2H, d), 7.44 (2H, d), 7.83 (1H, d), 9.27(1H, s), 10.31 (1H, s). m/z: ES+ [M+H]+ 360.

Preparation ofN-(4-Aminophenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide

4M Hydrogen chloride in dioxane (15.3 mL, 61.2 mmol) was added to amixture of tert-butyl(4-(2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamido)phenyl)carbamate (2.2g, 6.1 mmol) in DCM (20 mL) and methanol (20 mL). The mixture wasstirred at ambient temperature for 3 hours, during which time anadditional portion of 4M hydrogen chloride in dioxane (8.0 mL, 24 mmol)was added. The mixture was evaporated to dryness and the residuedissolved in water (70 mL). This aqueous solution was added slowly tostirred 1M potassium carbonate solution (150 mL), causing a white solidto precipitate. The mixture was stirred for 10 minutes at ambienttemperature. The precipitate was collected by filtration, washed withwater and dried under vacuum to afford the title compound as a whitesolid (1.4 g, 89%) which was used without purification. 1H NMR (500 MHz,DMSO, 27° C.) δ 1.23 (6H, d), 2.98 (1H, hept), 4.90 (2H, s), 5.14 (2H,s), 6.50 (2H, d), 7.20 (2H, d), 7.82 (1H, s), 9.99 (1H, s); m/z: ES+[M+H]+ 260.

Preparation of 2,6-Difluoro-4-(2-methoxyethoxy)benzonitrile

1-Bromo-2-methoxyethane (8.4 mL, 89 mmol) was added to a stirredsuspension of 2,6-difluoro-4-hydroxybenzonitrile (11.5 g, 74.1 mmol) andpotassium carbonate (30.7 g, 222.4 mmol) in DMF (175 mL). The mixturewas heated to 85° C. for 5 hours. The mixture was cooled to ambienttemperature and was poured into water (1250 mL). The mixture wasextracted with ethyl acetate (2×400 mL). The combined extracts werewashed with water (4×400 mL), saturated brine (200 mL), dried andevaporated to dryness to give an orange oil. The crude product waspurified by flash silica chromatography, elution gradient 20 to 45%ethyl acetate in heptane. Pure fractions were evaporated to dryness toafford the title compound as a white crystalline solid (16.1 g, 93%). 1HNMR (500 MHz. DMSO, 27° C.) δ 3.28 (3H, s), 3.62-3.68 (2H, m), 4.21-4.27(2H, m), 7.05-7.14 (2H, m); m/z: ES+ [M+H]+ 214.

Preparation of 2-Amino-6-fluoro-4-(2-methoxyethoxy)benzonitrile

2,6-Difluoro-4-(2-methoxyethoxy)benzonitrile (23 g, 107.9 mmol) wassplit between 14 microwave vials, each containing (1.64 g, 7.7 mmol)substrate. Each batch was suspended in isopropanol (3 mL) andconcentrated aqueous ammonia solution (8 mL, 3237 mmol) was added. Eachvial was capped and heated to 100° C. in microwave reactors for 13hours. All batches were combined; the solid which crystallised fromsolution was collected by filtration, washed with water and dried toafford the title compound as a white crystalline solid (19.6 g, 87%). 1HNMR (500 MHz, DMSO, 27° C.) δ 3.28 (3H, s), 3.57-3.64 (2H, m), 4.02-4.07(2H, m), 6.10 (1H, dd), 6.17 (1H, dd), 6.35 (2H, s); m/z: ES− [M−H]−209.

Preparation of(E)-N′-(2-Cyano-3-fluoro-5-(2-methoxyethoxy)phenyl)-N,N-dimethylformimidamide

1,1-Dimethoxy-N,N-dimethylmethanamine (62.6 ml, 471 mmol) was added to2-amino-6-fluoro-4-(2-methoxyethoxy)benzonitrile (11 g, 52.3 mmol) at25° C. The resulting solution was stirred at 80° C. for 2 hours, thencooled to room temperature. The mixture was poured into stirred water(200 mL) (exotherm, cold water cooling applied) and the reaction mixturestirred for 1 hour. The mixture was extracted with ethyl acetate (2×150mL). The combined extracts were washed with water (3×150 mL), saturatedbrine (100 mL), dried and evaporated to dryness to afford the titlecompound as a white crystalline solid (13.9 g, 100%). 1H NMR (500 MHz.DMSO, 27° C.) δ 2.98 (3H, s), 3.07 (3H, s), 3.29 (3H, s), 3.61-3.66 (2H,m), 4.14-4.17 (2H, m), 6.55-6.6 (2H, m), 8.03 (1H, s); m/z: ES+ [M+H]+266.

Form A of Compound X

The final product,N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide,was analysed by XRPD and DSC and found to be crystalline. XRPD of asample of the material gave rise to a diffraction pattern as shown inFigure A.N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamideForm A is characterised by at least one peak at a 2θ value of 6.7° and18.7°, measured using CuKα radiation. The ten most prominent peaks ofthe XRPD are shown in Table A.

TABLE A Ten most prominent XRPD peaks for N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide Form A Angle 2- Theta (2θ) Intensity % 6.7100.0 18.7 76.9 9.9 42.3 3.4 32.3 16.2 10.0 28.9 9.1 26.6 7.1 23.3 5.125.1 4.4 22.1 3.6 wherein the 2-theta values are +/−0.2°.

DSC analysis ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamideForm A showed a melting endotherm with an a melting endotherm with anonset of 235.7° C. and a peak at 237.6° C. A trace of the DSC is shownin Figure B.

Form B of Compound X

Form B material was produced by slurryingN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide,Form A in water at room temperature. Approximately 10 mg of the originalmaterial were placed in a 1.5 ml glass vial with a magnetic stirrer bar,and approximately 0.5 ml of water added, the vial was then sealedtightly with a cap and left to stir on a magnetic stirrer plate. Afterapproximately 4 days, the sample was removed from the plate, the captaken off and the slurry left to dry under ambient conditions before itwas analysed by XRPD, DSC and TGA. The resultant material (Form B) wasdetermined to be crystalline by XRPD. DSC and TGA analysis show thatthis material corresponds to a monohydrate. There was a 4.1% weight lossobserved on heating to 220° C. A trace ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamideis shown in Figure D.

XRPD of a sample of the material gave rise to a diffraction pattern asshown in Figure C.N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide,Form B is characterised by at least one peak at a 2θ value of 4.2° and7.7°, measured using CuKα radiation. The ten most prominent peaks of theXRPD are shown in Table B.

TABLE B Ten most prominent XRPD peaks for N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide Form B Angle 2- Theta (2θ) Intensity % 18.6100 9.8 35.7 6.6 29.5 13.1 23.0 13.7 20.5 7.7 19.0 26.5 15.7 4.2 13.028.8 12.8 20.0 11.8 wherein the 2-theta values are +/−0.2°.

Example 12.1 Scale up ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide1^(st) Arm of Convergence Route

Stage 1:

1-bromo-2-methoxyethane (65.4 mL, 696.31 mmol) was added in one portionto 2,6-difluoro-4-hydroxybenzonitrile (90 g, 580.26 mmol) and potassiumcarbonate (241 g, 1740.77 mmol) in DMF (1200 mL). The resulting solutionwas stirred at 85° C. for 5 hours.

The reaction mixture was poured into water (400 mL), extracted withEtOAc (2×200 mL), the organic layer was dried over Na₂SO₄, filtered andevaporated to afford crude product.

The crude product was purified by flash silica chromatography, elutiongradient 20 to 30% EtOAc in petroleum ether. Pure fractions wereevaporated to dryness to afford2,6-difluoro-4-(2-methoxyethoxy)benzonitrile (115 g, 93%) as a yellowoil. 1H NMR (400 MHz, DMSO-d6) δ 7.17-7.08 (m, 2H), 4.29-4.22 (m, 2H),3.70-3.61 (m, 2H), 3.30 (s, 3H).

Stage 2:

Aqueous ammonia solution (360 ml, 16.64 mol) was added to2,6-difluoro-4-(2-methoxyethoxy)benzonitrile (56 g, 0.26 mol) in iPrOH(120 mL) at room temperature. The resulting solution was stirred at 95°C. for 12 hours.

A solid crystallised from solution, the solid was collected byfiltration. The solid was washed with 15% isopropanol in water, thenwashed with water and dried. This resulted in2-amino-6-fluoro-4-(2-methoxyethoxy)benzonitrile (50.8 g, 92%) as awhite solid. 1H NMR (DMSO-d6, 400 MHz) δ 3.29 (3H, s), 3.59-3.66 (2H,m), 4.03-4.10 (2H, m), 6.09-6.23 (2H, m), 6.38 (2H, s).

Stage 3:

DMF-DMA (500 ml, 3734.35 mmol) was added to2-amino-6-fluoro-4-(2-methoxyethoxy)benzonitrile (90 g, 428.15 mmol).The resulting solution was stirred at 80° C. for 2 hours.

The reaction mixture was poured into ice water (1.5 L), extracted withEtOAc (3×500 mL), the organic layer was dried over Na₂SO₄, filtered andevaporated to afford(E)-N′-(2-cyano-3-fluoro-5-(2-methoxyethoxy)phenyl)-N,N-dimethylformimidamide(110 g, 97%) as a colourless solid. 1H NMR (DMSO-d6, 400 MHz) δ 3.04(6H, d), 3.61-3.69 (2H, m), 4.13-4.21 (2H, m), 6.55-6.63 (2H, m), 8.05(1H, s).

2^(nd) Arm of Convergence Route

Stage 4:

The process of this stage was run in parallel. A solution of 30% ethyl2-azidoacetate in DCM (60 g, 464.69 mmol) was mixed with acetonitrile(500 mL) and then added dropwise to a stirred solution of3-methylbut-1-yne (36.4 g, 534.39 mmol), copper(I) iodide (1.770 g, 9.29mmol) and TEA (1.295 mL, 9.29 mmol) in acetonitrile (500 mL) at 22° C.,over a period of 5 minutes under nitrogen. The resulting solution wasstirred at 22° C. for 12 hours.

The resulting solutions were then combined and the solvent was removedunder reduced pressure. The crude product was purified by flash silicachromatography, elution gradient 0 to 40% EtOAc in petroleum ether. Purefractions were evaporated to dryness to afford ethyl2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetate (160 g, 175%) as acolourless oil. 1H NMR (Chloroform-d, 300 MHz) δ 1.06-1.18 (9H, m),2.88-2.97 (1H, m), 4.07 (2H, q), 4.99 (2H, s), 7.35 (1H, d).

Stage 5:

A solution of LiOH (38.9 g, 1622.41 mmol) in water (200 mL) was addeddropwise to a stirred solution of ethyl2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetate (160 g, 811.20 mmol) in THF(800 mL) at 22° C., over a period of 5 minutes under nitrogen. Theresulting solution was stirred at 22° C. for 12 hours.

The solvent was removed under reduced pressure. The reaction mixture wasacidified with 2M HCl to pH 6. The solid was collected and dried undervacuum at 40° C. to give 2-(4-isopropyl-1H-1,2,3-triazol-1-yl)aceticacid (120 g, 87%) as a white solid. 1H NMR (Methanol-d4, 300 MHz) δ 1.33(6H, d), 3.04-3.09 (1H, m), 4.93 (2H, s), 7.69 (1H, d).

Stage 6:

HATU (147 g, 386.88 mmol) was added to tert-butyl(4-aminophenyl)carbamate (67.1 g, 322.40 mmol),2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetic acid (60 g, 354.64 mmol) andDIPEA (84 mL, 483.60 mmol) in DMF (200 mL). The resulting solution wasstirred at room temperature for 12 hours.

The reaction mixture was poured into water (600 ml). The resulting solidprecipitate was collected by filtration and dried to give a light purplesolid.

The solid was recrystallised from acetonitrile to afford tert-butyl(4-(2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamido)phenyl)carbamate (105g, 91%) as white solid. 1H NMR (DMSO-d6, 40) MHz) δ 1.25 (6H, d), 1.47(9H, s), 2.94-3.04 (1H, m), 5.22 (2H, s), 7.36-7.50 (4H, m), 7.85 (1H,d), 9.30 (1H, s), 10.33 (1H, s).

Stage 7:

HCl (4M in dioxane) (598 mL, 2392.68 mmol) was added to tert-butyl(4-(2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamido)phenyl)carbamate (86g, 239.27 mmol) in DCM (400 mL) and MeOH (400 ml). The resultingsolution was stirred at 25° C. for 16 hours. The solvent was removedunder reduced pressure. The reaction mixture was diluted with DCM. Thereaction mixture was adjusted to pH 10 with saturated Na₂CO₃. Theprecipitate was collected by filtration, washed with water (300 mL) anddried under vacuum to affordN-(4-aminophenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide (51.0g, 82%) as a white solid, which was used without further purification.1H NMR (400 Hz. DMSO) δ: 1.24 (6H, d), 2.96-3.02 (1H, m), 5.11-5.16 (4H,m), 6.53 (2H, d), 7.23 (2H, d), 7.83 (1H, s), 10.04 (1H, s).

Convergence

Example 12

(E)-N′-(2-cyano-3-fluoro-5-(2-methoxyethoxy)phenyl)-N,N-dimethylformimidamide(37.6 g, 141.91 mmol) was added toN-(4-aminophenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide (46 g,177.39 mmol) in acetic acid (300 mL). The resulting solution was stirredat 60° C. for 40 minutes.

This reaction was combined with two other batches for isolation andpurification which were synthesised according to the process describedin the paragraph above.

The reaction mixture was poured into ice water. The precipitate wascollected by filtration, washed with water (200 mL) and dried undervacuum to afford crude product.

The crude product was recrystallized with EtOH and dried to affordN-(4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide(45.0 g, 66.1%) as white solid. 1H NMR (DMSO-d6, 400 MHz) δ 1.26 (6H,d), 2.93-3.07 (1H, m), 3.33 (3H, s), 3.68-3.75 (2H, m), 4.24-4.32 (2H,m), 5.29 (2H, s), 7.05 (1H, d), 7.14 (1H, q), 7.57-7.64 (2H, m),7.63-7.72 (2H, m), 7.89 (1H, d), 8.46 (1H, s), 8.98 (1H, d), 10.50 (1H,s).

Example 12A Scale up of Tosylate Salt ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide

Stage 1:

1-bromo-2-methoxyethane (9.6 kg, 69.06 mol) was added in one portion to2,6-difluoro-4-hydroxybenzonitrile (8.6 kg, 55.45 mol) and potassiumcarbonate (23 kg, 166.43 mol) in CH₃CN (70.9 kg). The resulting solutionwas stirred at 80-85° C. for 8-10 hours.

The reaction mixture was cooled to 40-45° C. and filtered. The cake waswashed with CH₃CN (13.4 kg). The combined filtrate was concentratedunder vacuum to 34-43 L. Process water (92.0 kg) was added and themixture was concentrated under vacuum to 77-85 L. The suspension wasfiltered to afford 2,6-difluoro-4-(2-methoxyethoxy)benzonitrile (13.70kg, 100%) as a damp solid. 1H NMR (400 MHz. DMSO-d6) δ 3.29 (3H, s),3.65-3.67 (2H, t), 4.24-4.26 (2H, t), 7.11 (1H, s), 7.14 (1H, s)

Stage 2:

25% Aqueous ammonia solution (187.8 kg, 1341.43 mol) was added to2,6-difluoro-4-(2-methoxyethoxy)benzonitrile (13.7 kg, 56.68 mol, assay:88.2%) in iPrOH (42.6 kg) at room temperature. The resulting solutionwas stirred at 100-110° C. for 16-20 hours in autoclave.

A solid was crystallized from solution and was collected by filtration.The solid was washed with 15% isopropanol in water and dried. Thisresulted in 2-amino-6-fluoro-4-(2-methoxyethoxy)benzonitrile (7.4 kg,62%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 3.29 (3H, s),3.61-3.63 (2H, t), 4.04-4.07 (2H, t), 6.11 (1H, s), 6.16-6.19 (1H, d),6.37 (2H, s)

Stage 3:

DMF-DMA (16.8 kg, 140.99 mol) was added to2-amino-6-fluoro-4-(2-methoxyethoxy)benzonitrile (7.4 kg, 35.20 mol) inMTBE (46.8 kg). The resulting solution was stirred at 55-60° C. for 6-8hours.

The reaction mixture was cooled to 20-30° C. and washed with brine.Molecular sieves (11.0 kg) was added to the organic phase to removewater. The organic solution was concentrated under vacuum to 37-44 Lfollowed by the addition of MTBE to afford(E)-N′-(2-cyano-3-fluoro-5-(2-methoxyethoxy)phenyl)-N,N-dimethylformimidamidesolution (53.25 kg, assay: 15.9%, 91%). 1H NMR (DMSO-d6, 400 MHz) δ 2.99(3H, s), 3.08 (3H, s), 3.30 (3H, s), 3.64-3.67 (2H, t), 4.15-4.18 (2H,t), 6.57-6.60 (2H, m), 8.04 (1H, s)

Stage 4:

tert-butyl (4-aminophenyl)carbamate (8.4 kg, 40.33 mol) was added to(E)-N′-(2-cyano-3-fluoro-5-(2-methoxyethoxy)phenyl)-N,N-dimethylformimidamidesolution (9.0 kg, 33.92 mol) in MTBE (30 kg). AcOH (31.6 kg) was addedthen. The resulting solution was stirred at 50-60° C. for 3-4 hours.

The reaction mixture was cooled to 20-30° C. and filtered. MTBE (26 kg)was used to wash the cake. The solid was dried to afford tert-butyl(4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)carbamate(13.10 kg, assay: 87.5%, 79%). 1HNMR (DMSO-d6, 400 MHz) δ 1.49 (9H, s),3.3 (3H, s), 3.70-3.72 (2H, t), 4.27-4.29 (2H, t), 7.04 (1H, s),7.11-7.15 (1H, dd), 7.43-7.56 (4H, m), 8.42 (1H, s), 8.90-8.93 (1H, d),9.35 (1H, s)

Stage 5:

HCl gas (85 kg, 2328.77 mol) was added to tert-butyl(4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)carbamate(10.2 kg, 23.80 mol) in 2-MeTHF (160 kg) and water (10 kg). Theresulting solution was stirred at 20-25° C. for 4-6 hours.

The reaction mixture was filtered and washed with 2-MeTHF (40 kg). Thesolid was dried to affordN1-(5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)benzene-1,4-diaminedihydrochloride (9.10 kg, 95%). 1H NMR (DMSO-d6, 400 MHz) δ 3.33 (3H,s), 3.72-3.74 (2H, t), 4.30-4.35 (2H, t), 7.29-7.62 (6H, m), 8.79 (1H,s), 10.57 (2H, brs)

Stage 6:

25% Aqueous ammonia solution (27 kg, 192.86 mol) was added toN1-(5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)benzene-1,4-diaminedihydrochloride (9.10 kg, 22.68 mol) in water (150 kg). The resultingsolution was stirred at 20-25° C. for 2-3 hours.

The reaction mixture was filtered and washed with water (60 kg). Thesolid was dried to affordN1-(5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)benzene-1,4-diamine(6.15 kg, 83%). 1HNMR (DMSO-d6, 400 MHz) δ 3.3 (3H, s), 3.70-3.72 (2H,t), 4.25-4.29 (2H, t), 5.07 (2H, s), 6.56-6.59 (2H, d), 7.00 (1H, s),7.09-7.10 (1H, d), 7.23-7.25 (2H, d), 8.35 (1H, s), 8.69-8.72 (1H, d)

Stage 7:

N-[5-fluoro-7-(2-methoxyethoxy)-4-quinazolinyl]-1,4-benzenediamine(4.184 kg, 12.5 mol) was charged with[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetic acid (2.41 kg, 13.8 mol)and acetonitrile (62 L) and heated to 65° C. N-ethyldiisopropylamine(4.36 L, 25.0 mol) was charged with 1-propanephosphonic anhydride 50% inacetonitrile (9.96 kg, 16.3 mol) at <80° C. The mixture was stirred at65° C. and then cooled to 10-20° C. and 2-propanol (20.5 L) was added.The mixture was then cooled to 0-10° C. before filtering, washing withacetonitrile (2×10 L) and then drying to affordN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide(5.530 kg, 91.1%) as an off white solid. 1H NMR (500 MHz, DMSO-d6) δ1.2(d, 6H) 3.0 (spt, 1H) 3.3 (s, 3H) 3.7-3.7 (m, 2H) 4.2-4.3 (m, 2H) 5.3(s, 2H) 7.0 (d, 1H) 7.1 (dd, 1H) 7.5-7.6 (m, 2H) 7.6-7.7 (m, 2H) 7.9 (s,1H) 8.4 (s, 1H) 9.0 (d, 1H) 10.5 (s, 1H)

Stage 8:

N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide(2 kg, 4.13 mol) and p-toluenesulfonic acid (0.842 kg, 4.34 mol) areheated with agitation in a mixture of propan-2-ol (26 L, 340 mol) anddimethylsulfoxide (6.5 L, 92 mol) until a solution is formed. Theresulting solution is filtered hot and the filtrate cooled and seededwithN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidetosylate, the seed was prepared according to the method described belowunder the heading “Form A of Tosylate Salt Y”. The resultingN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidetosylate is filtered under reduced pressure and the filter cake washedwith a mixture of propan-2-ol (0.4 L, 5 mol) and dimethylsulfoxide (0.1L, 1 mol). After deliquoring of the filter cake and final filter cakewashing with propan-2-ol the solids are dried in the vacuum oven toprovideN-(4-{[5-Fluoro-7-(2-methoxyethoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidetosylate (2.458 kg, 91.2%) as a bright yellow solid. 1H NMR (500 MHz,DMSO-d6) δ1.2 (d, 6H) 2.3 (s, 3H) 3.0 (spt, 1H) 3.3 (s, 3H) 3.7-3.8 (m,2H) 4.3-4.4 (m, 2H) 5.3 (s, 2H) 7.0-7.1 (m, 3H) 7.4-7.6 (m, 5H) 7.6-7.7(m, 2H) 7.9 (s, 1H) 8.8 (s, 1H) 10.5 (br d, 1H) 10.6 (s, 1H)

Scheme 5:

The [4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetic acid used in Stage 7of Scheme 4 was prepared by the method depicted in Scheme 5. A solutionof methyl 2-bromoacetate (5.4 kg, 36 mol) in 2-propanol (19 L) andsodium azide (2.3 kg, 35 mol) in water (23 L) were reacted in an AlfaLaval flow reactor at 120° C. with a residence time of 40 seconds, thereaction was monitored by PAT (IR and RAMAN). The output feed was thenfurther reacted with a solution feed containing 3-methylbut-1-yne (3.1kg, 44 mol) with copper iodide (0.21 kg) and trimethylamine (1.1 kg) inpyridine (8.1 L) at 80° C. with residence time of 152 seconds. Theoutput (monitored by PAT IR) is collected in in an agitated vessel alongwith a solution feed containing di-sodium edetate (2.9 kg), sodiumnitrite (0.14 kg) and sodium hydroxide (5 kg, 58 mol) in water (7.95 L).The resulting suspension is filtered under reduced pressure. Tert-butylmethyl ether (45 L) is added to the filtrate and the mixture agitatedfor 30 minutes. The agitation is stopped and the layers allowed toseparate and the aqueous layer collected. The aqueous layer is acidifiedby slow addition of aqueous sulfuric acid (3.5 M) with agitationmaintaining the temperature at <26° C. until a pH of 2.5 is achieved.2-Methyltetrahydrofuran (32.5 L) is then added and the mixture agitatedfor a further 10 minutes. The agitation is stopped and the layersallowed to separate. The organic layer is collected.2-Methyltetrahydrofuran (33 L) is added to the resulting aqueous layerand the mixture agitated for 10 minutes. The agitation is stopped andthe layers allowed to separate and the organic layer collected. Theresulting aqueous layer is adjusted to a pH of 2.5 with 3.5 M HCl withagitation and 2-methyltetrahydrofuran (16 L) added and the mixtureagitated for 10 minutes. The agitation is stopped and the layers allowedto separate. The organic layer is collected and combined with thepreviously collected 2-methyltetrahydrofuran organic extracts. Thecombined organic extracts are distilled at atmospheric pressure toremove 15 relative volumes (48.6 L) of organics. Further2-methyltetrahydrofuran (33 L) is added to the remaining organics andthe mixture distilled at atmospheric pressure to remove a further 12relative volumes (40 L) of organics. The remaining organics are cooledto 70° C. with agitation then ramp cooled to 0° C. over the course of 4hours. Tert-butyl methyl ether (13 L) is added over 20 minutes and themixture agitated at 0° C. for 3 hours. The resulting suspension isfiltered under reduced pressure. The filter cake is washed withpre-cooled (0° C.) tert-butyl methyl ether (13 L) and the filter cakepulled dry. The resulting solids are dried in the vacuum oven (40° C.)to provide [4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetic acid as a whitecrystalline solid (6.2 kg, 40%). 1H NMR (DSMO-d6, 500 MHz): 13.3 (1H, brs, OH) 7.82 (1H, s, 5-H), 5.21 (2H, s, CH₂CO₂H), 2.99 (1H, hept, J=5 Hz,CHMe₂), 1.24 (6H, d, J=5 Hz, 2×Me). 13C NMR (DMSO-d6, 125 MHz): 168.9(C═O), 153.1 (C, C-4), 121.9 (CH, C-5), 50.45 (CH₂, CH₂CO₂H), 23.32 (CH,CHMe₂), 22.51 (CH₃, 2×Me). UPLC MS (BEH/MeCN/TFA): Rt=0.61 min (λmax=221.1). Mass spectrum: 170.06 (M+H), 154.05 (M−CH₃), 125.9 (M−CO₂),112.0 (M−CH₂CO₂H).

Form A of Tosylate Salt Y

N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidepure free base and p-toluenesulfonic acid monohydrate were dissolved in16 relative volumes of 20% dimethylsulfoxide:propan-2-ol at 20° C. SeedofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidetosylate salt Form A (0.02%) was added to the vessel and the contents ofthe vessel were heated to 75° C. over a minimum of 60 minutes. Theresulting solution was screened into a crystalliser at 75° C. via aninline filter. Resulting solution was cooled to 40° C. over 20 minutesand propan-2-ol (6.5 relative volumes) was added dropwise to thereaction vessel as an antisolvent to bring the solvent composition to15% dimethylsulfoxide:propan-2-ol. The crystalliser was seeded againwithN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidetosylate salt Form A (0.06%) while the slurry was at 40° C. The slurrywas kept stirring at 40° C. for 3 days. XRPD analysis was carried out tocheck for polymorphic form. The resultant slurry was filtered, washedwith 15% dimethylsulfoxide:propan-2-ol and the solid was dried in thevacuum oven at 40° C. until constant weight was obtained. The resultingpowder was sampled for XRPD and HPLC for polymorphic form and puritycheck respectively, and the loss to liquors was also determined.

In certain circumstances, an additional step may be required, whichinvolves suspending the material in isopropyl acetate, seeding withN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidetosylate salt Form A and slurrying at 80° C. for 24 hours. The resultingmaterial is analysed by XRPD to confirm formation of Form A, isolatedand dried as described above. Form A is characterised by at least onepeak at 2θ value of 13.4° and 14.3°, measured using CuKα radiation. Theten most prominent peaks of the XRPD are shown in Table C.

Seed ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidetosylate Salt Form A

The seed used in the method described above for Form A of Tosylate SaltY was obtained as follows:N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidepure free base was added to a Duran bottle and 20 relative volumes ofethyl acetate were added to the bottle while stirring to create aslurry. A solution of p-toluenesulfonic acid monohydrate (1.1equivalent) was made by fully dissolving it in 40 relative volumes ofethyl acetate. The p-toluenesulfonic acid solution was added dropwise tothe API solution while stirring vigorously. The resulting yellowmaterial was subjected to slurrying under ambient conditions for 5 daysin the capped Duran bottle. The resulting material was checked by XRPDto show the formation of a highly crystalline material that correspondedto a 1:1N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidetosylate salt following analysis by NMR, DSC and X-ray crystal structureelucidation. The solid was isolated by vacuum filtration and dried in avacuum oven.

TABLE C Ten most prominent XRPD peaks for N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide tosylate salt Form A Angle 2- Theta (2θ)Intensity % 11.7 100 20.2 74.6 12.2 51.4 21.4 36.6 23.6 30.1 23.7 29.424.4 25.9 17.3 22.3 14.3 11.1 13.4 9.7 wherein the 2-theta values are+/−0.2°.

Form B of Tosylate Salt Y

Form B of Tosylate Salt Y is a hydrated form obtained from salt scale-upexperiments in ethanol, seeded with Form C of Tosylate Salt Y.

Form B was obtained by exposing Form C of Tosylate Salt Y to highhumidity levels such as in a DVS experiment. Alternatively, Form B wasobtained during a salt scale-up experiment in ethanol.N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidepure free base and p-toluenesulfonic acid monohydrate were added in a 1litre glass reactor equipped with an overhead stirrer. Ten relativevolumes of ethanol were added to the reactor at 20° C. The contents ofthe vessel were heated to 75° C. over 2 hours to obtain a clear yellowsolution. The contents of the reactor were cooled to 60° C. over 20minutes. 1% of the mixture of Forms C and B, obtained from the Form Cmethod outlined in the section below, was added to the reactor whilestirring. Contents were held at 60° C. for 5 hours followed by coolingto 5° C. over 10 hours. The solid was isolated at 5° C. by vacuumfiltration, washed with chilled ethanol and dried in a vacuum oven at20° C. overnight, followed by a 25 minute drying period at 40° C. Theresulting solid was analysed by XRPD and gave a crystalline form namedForm B. Form B is characterised by at least one peak at 20 value of 4.2°and 7.7°, measured using CuKα radiation. The ten most prominent peaks ofthe XRPD are shown in Table D.

TABLE D Ten most prominent XRPD peaks for N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide tosylate salt Form B Angle 2- Theta (2θ)Intensity % 11.8 100 19.4 88.2 25.2 84.2 7.1 61.7 20.9 61 14.2 54 20.443.2 23.9 37.2 22.5 32.8 9.2 11 wherein the 2-theta values are +/−0.2°.

Form C of Tosylate Salt Y

Form C of Tosylate Salt Y is an ethanol solvate form obtained fromsolubility measurement experiments in ethanol and acetonitrile.

Form C was obtained during solubility measurement experiments startingwith Form A of Tosylate Salt Y. Solubility curves were generated inethanol and acetonitrile. Different masses of Form A were added in vialsand stirred in ethanol and acetonitrile. The heating ramp was set from25° C. to 75° C. at a rate of 0.03° C./minute. All materials went intosolution at elevated temperatures. The solutions were cooled back to 25°C. at a rate of 0.03° C./minute and solid was recrystallised in thevials at different points of the cooling cycle. The resulting solidswere analysed by XRPD as slurries and gave a crystalline form named FormC. Form C is not a stable form and will convert to Form B both duringvacuum drying and under ambient conditions. Therefore, it is common toisolate a mixture of Forms C and B that will eventually convert to FormB through evaporation of ethanol from the crystal structure. Theisolated mixture of Forms C and B can be used as a seed in the methodfor obtaining Form B, described in the section above.

Form D of Tosylate Salt Y

Form D of Tosylate Salt Y is a dimethylsulfoxide solvate form obtainedfrom salt scale-up experiments in 20% dimethylsulfoxide:propan-2-ol.

Form D was obtained by crystallisation from aN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamidetosylate salt saturated solution in 20% dimethylsulfoxide:propan-2-ol.Initially, the solvent system used for obtaining Form A was 20%dimethylsulfoxide:propan-2-ol. It was later realised thatrecrystallization from the mother liquor after initial Form A isolationin the above solvent system yielded Form D. The amount ofdimethylsulfoxide in the solvent mixture for obtaining Form A wastherefore reduced from 20% to 15% to ensure that Form A is obtained.Form A is obtained at a temperature of 40° C. while Form D is obtainedat temperatures below 25° C. Form D is characterised by at least onepeak at 2θ value of 4.4° and 5.6°, measured using CuKα radiation. Theten most prominent peaks of the XRPD are shown in Table E.

TABLE E Ten most prominent XRPD peaks for N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide tosylate salt Form D Angle 2- Theta (2θ)Intensity % 4.4 100 8.8 96.2 19.1 53.8 24.8 23.7 16.8 18.3 26.9 17.422.3 15.9 5.6 15.6 21.9 14.5 19.7 14.4 wherein the 2-theta values are+/−0.2°.

Example 13 and Example 14(R)-2-(4-Isopropyl-1H-1,2,3-triazol-1-yl)-N-(4-((5-methoxy-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)phenyl)acetamideand(S)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)-N-(4-((5-methoxy-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)phenyl)acetamide

Potassium tert-butoxide (150 mg, 1.4 mmol) was added totetrahydrofuran-3-ol (121 mg, 1.4 mmol) andN-(4-((7-fluoro-5-methoxyquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide(300 mg, 0.7 mmol) in DMF (3 mL) at 25° C. under nitrogen. The resultingmixture was stirred at 80° C. for 5 hours. The reaction mixture wascooled to room temperature and filtered to give a crude residue. Theresidue was purified by flash silica chromatography, elution gradient 0to 10% methanol in DCM. Pure fractions were evaporated to dryness toafford crude product as a yellow solid. The crude product was purifiedby preparative HPLC. Fractions containing the desired compound wereevaporated to dryness to afford racemic title compound as a pale yellowsolid (150 mg, 43%). The racemic product was purified by preparativechiral-HPLC on a Chiralpak IB column, eluting isocratically with 30%isopropanol in TBME (modified with 0.1% DEA) as eluent. The fractionscontaining the desired compound were evaporated to dryness to afford oneenantiomer of2-(4-isopropyl-1H-1,2,3-triazol-1-yl)-N-(4-((5-methoxy-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)phenyl)acetamideas a pale yellow solid (52 mg, 15%, >99.9% e.e.). 1H NMR (300 MHz,DMSO-d6) δ 1.25 (6H, d), 1.97-2.11 (1H, m), 2.27-2.41 (1H, m), 2.94-3.06(1H, m), 3.75-4.00 (4H, m), 4.11 (3H, s), 5.22-5.28 (1H, m), 5.29 (2H,s), 6.80-6.84 (2H, m), 7.61 (2H, d), 7.67 (2H, d), 7.88 (1H, s), 8.62(1H, s), 10.43 (1H, s), 10.65 (1H, s); m % z (ES+), [M+H]+=504; acid,HPLC tR=1.35 min. This was followed by the other enantiomer of2-(4-isopropyl-1H-1,2,3-triazol-1-yl)-N-(4-((5-methoxy-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)phenyl)acetamideas a pale yellow solid (51 mg, 15%, 98.7% e.e.). 1H NMR (300 MHz,DMSO-d6) δ 1.25 (6H, d), 1.96-2.10 (1H, m), 2.25-2.39 (1H, m), 2.94-3.06(1H, m), 3.74-3.98 (4H, m), 4.08 (3H, s), 5.20-5.26 (1H, m), 5.27 (2H,s), 6.67 (1H, d), 6.75 (1H, d), 7.60 (2H, d), 7.77 (2H, d), 7.88 (1H,s), 8.41 (1H, s), 9.80 (1H, s), 10.49 (1H, s); m/z (ES+), [M+H]+=504;acid, HPLC tR=1.35 min.

Example 15N-(4-{[5-Methoxy-7-(propan-2-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide

Sodium hydride (41 mg, 1 mmol) was added toN-(4-((7-fluoro-5-methoxyquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide(150 mg, 0.3 mmol) and isopropanol (62.1 mg, 1 mmol) in DMF (1.5 mL) at25° C. under nitrogen. The resulting solution was stirred at roomtemperature for 1 hour. The resulting solution was stirred at 80° C. for7 hours. The reaction mixture was filtered. The crude product waspurified by preparative HPLC. Fractions containing the desired compoundwere evaporated to dryness to afford the title compound as a white solid(72 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ 1.26 (6H, d), 1.35 (6H, d),2.94-3.07 (1H, m), 4.08 (3H, s), 4.77-4.90 (1H, m), 5.27 (2H, s), 6.64(1H, d), 6.77 (1H, d), 7.60 (2H, d), 7.78 (2H, d), 7.88 (1H, s), 8.40(1H, s), 9.77 (1H, s), 10.49 (1H, s) m/z (ES+), [M+H]+=476; acid. HPLCtR=6.90 min.

Example 16N-(4-{[5-Methoxy-7-(oxetan-3-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide

Potassium tert-butoxide (52 mg, 0.5 mmol) was added to oxetan-3-ol (34mg, 0.5 mmol) andN-(4-((7-fluoro-5-methoxyquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide(100 mg, 0.2 mmol) in DMF (0.5 mL) at 25° C. under air. The resultingmixture was stirred at 80° C. for 5 hours. The crude product waspurified by preparative HPLC. Fractions containing the desired compoundwere evaporated to dryness to afford the title compound (42 mg, 37%) asan off-white solid. 1H NMR (300 MHz, DMSO, 23° C.) δ 1.25 (6H, d),2.94-3.06 (1H, m), 4.10 (3H, s), 4.59 (2H, t), 5.00 (2H, t), 5.26 (2H,s), 5.42-5.50 (1H, m), 6.45 (1H, s), 6.72 (1H, s), 7.58-7.60 (2H, m),7.75-7.77 (2H, m), 7.87 (1H, s), 8.40 (1H, s), 9.78 (1H, s), 10.48 (1H,s). m/z (ES+), [M+H]+=490; TFA, HPLC tR=2.319 min.

Example 17N-[4-({7-[2-(Dimethylamino)ethoxy]-5-methoxyquinazolin-4-yl}amino)phenyl]-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide

Potassium tert-butoxide (52 mg, 0.5 mmol) was added toN-(4-((7-fluoro-5-methoxyquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide(100 mg, 0.2 mmol) and 2-(dimethylamino)ethan-1-ol (31 mg, 0.3 mmol) inDMF (1 mL) at 25° C. under nitrogen. The resulting solution was stirredat 100° C. for 3 hours. The reaction mixture was purified by flashsilica chromatography, elution gradient 0 to 10% methanol (1M NH₃) inDCM. Pure fractions were evaporated to dryness to afford crude productas a yellow solid. The crude product was purified by preparative HPLC.Fractions containing the desired compound were evaporated to dryness toafford the title compound as a white solid (36 mg, 31%). 1H NMR (300MHz, DMSO-d6) δ 1.25 (6H, d), 2.24 (6H, s), 2.67 (2H, t), 2.92-3.06 (1H,m), 4.08 (3H, s), 4.19 (2H, t), 5.27 (2H, s), 6.68 (1H, d), 6.79 (1H,d), 7.59 (2H, d), 7.78 (2H, d), 7.88 (1H, d), 8.40 (1H, s), 9.78 (1H,s), 10.48 (1H, s); m/z (ES+), [M+H]+=505; acid, HPLC tR=1.12 min.

Example 18N-{4-[(7-Ethoxy-5-methoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide

Sodium ethoxide (in ethanol) (66 mg, 1 mmol) was added toN-(4-((7-fluoro-5-methoxyquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide(85 mg, 0.2 mmol) in DMF (5 mL) at room temperature. The resultingsolution was stirred at 80° C. for 3 hours. The reaction mixture waspoured into saturated aqueous NH₄Cl (100 mL). The mixture was filteredand the crude product was purified by preparative HPLC. Fractionscontaining the desired compound were evaporated to dryness to afford thetitle compound as a light yellow solid (30 mg, 33%). 1H NMR (DMSO-d6,400 MHz) δ 1.26 (6H, d), 1.40 (3H, t), 2.93-3.08 (1H, m), 4.08 (3H, s),4.18 (2H, d), 5.27 (2H, s), 6.73 (2H, dd), 7.60 (2H, d), 7.78 (2H, d),7.88 (1H, s), 8.41 (1H, s), 9.78 (1H, s), 10.49 (1H, s); m/z (ES+),[M+H]+=462; acid. HPLC tR=1.406 min.

Example 19N-{4-[(5,7-Diethoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide

HATU (140 mg, 0.4 mmol) was added to4-((5,7-diethoxyqunazoinazolin-4-yl)oxy)aniline (260 mg, 0.3 mmol),2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetic acid (79 mg, 0.3 mmol) andDIPEA (0.12 mL, 0.7 mmol) in DMF (3 mL) at 23° C. under nitrogen. Theresulting solution was stirred at room temperature for 1 hour. Thesolvent was removed under reduced pressure. The crude product waspurified by flash silica chromatography, elution gradient 0 to 8%methanol in DCM. Pure fractions were evaporated to dryness to affordcrude product as a yellow solid. The crude product was purified bypreparative HPLC. Fractions containing the desired compound wereevaporated to dryness to afford the title compound as a white solid (97mg, 61%). 1H NMR (400 MHz, DMSO-d6) δ 1.25 (6H, d), 1.39 (3H, t), 1.57(3H, t), 2.95-3.06 (1H, m), 4.11-4.24 (2H, m), 4.26-4.40 (2H, m), 5.27(2H, s), 6.68 (1H, d), 6.76 (1H, d), 7.61 (2H, d), 7.79 (2H, d), 7.88(1H, s), 8.44 (1H, s), 9.97 (1H, s), 10.51 (1H, s); m/z (ES+),[M+H]+=476; acid. HPLC tR=1.48 min.

The intermediates used in Example 19 were prepared as follows:

Preparation of 5,7-Diethoxyquinazolin-4(3H)-one

Sodium ethoxide (2.6 g, 7.9 mmol) was added to7-fluoro-5-methoxyquinazolin-4(3H)-one (1.4 g, 7.2 mmol) in DMF (15 mL)under nitrogen. The resulting solution was stirred at 80° C. for 5hours. The reaction mixture was poured into ice water. The resultingprecipitate was collected by filtration, washed with cold water (100mL), ether (50 ml) and dried under vacuum to afford a solid. The crudeproduct was purified by preparative HPLC. Fractions containing thedesired compound were evaporated to dryness to afford firstly7-ethoxy-5-methoxyquinazolin-4(3H)-one (0.5 g, 29%). 1H NMR (DMSO-d6,300 MHz) δ 1.38 (3H, t), 3.83 (3H, s), 4.16 (2H, q), 6.53 (1H, d), 6.65(1H, d), 7.92 (1H, s), 11.78 (1H, s) followed by5,7-diethoxyquinazolin-4(3H)-one as a white solid (0.2 g, 9%). 1H NMR(DMSO-d6, 300 MHz) δ 1.35 (6H, t), 4.10 (4H, dq), 6.49 (1H, d), 6.61(1H, d), 7.88 (1H, s), 11.71 (1H, s).

Preparation of N1-(5,7-Diethoxyquinazolin-4-yl)benzene-1,4-diamine

DBU (0.27 mL, 1.8 mmol) was added to 5,7-diethoxyquinazolin-4(3H)-one(160 mg, 0.7 mmol) and BOP (393 mg, 0.9 mmol) in acetonitrile (5 mL) atroom temperature under nitrogen. The resulting solution was stirred at60° C. for 1 hour. Para-Phenylenediamine (148 mg, 1.4 mmol) was added.The resulting solution was stirred at 60° C. for 5 hours. The reactionmixture was concentrated and diluted with DCM (100 mL), and washedsequentially with saturated aqueous NH₄Cl (10 mL), water (10 mL), andsaturated NaHCO₃ (10 mL). The organic layer was dried, filtered andevaporated to afford crude product. The crude product was purified byflash silica chromatography, elution gradient 0 to 4% methanol in DCM.Pure fractions were evaporated to dryness to afford the title compoundas a yellow solid (280 mg, >100%). 1H NMR (400 MHz, DMSO-d6) δ 1.38 (3H,t), 1.54 (3H, t), 4.12-4.18 (2H, m), 4.24-4.37 (2H, m), 5.60 (2H, s),6.58 (1H, s), 6.61 (2H, d), 6.70 (1H, s), 7.39 (2H, d), 8.33 (1H, s),9.68 (1H, s); m/z (ES+), [M+H]+=325; base, HPLC tR=0.83 min.

Example 20

N-(4-{[5-Methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide

HATU (10 mg, 0.03 mmol) was added toN1-(5-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)benzene-1,4-diamine(1.5 g, 4.4 mmol), 2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetic acid (1.1g, 4.9 mmol) and DIPEA (1.1 g, 8.8 mmol) in DMF (30 mL). The resultingmixture was stirred at room temperature for 2 hours. The reactionmixture was diluted with water. The resulting precipitate was collectedby filtration, washed with acetonitrile/H₂O (1:10, 50 mL) and driedunder vacuum, The crude product was purified by crystallisation fromacetonitrile to afford the title compound as a pale yellow solid (1.5 g,70%). 1H NMR (400 MHz, DMSO-d6) δ 1.25 (6H, d), 2.93-3.07 (1H, m), 3.33(3H, s), 3.65-3.77 (2H, m), 4.09 (3H, s), 4.20-4.30 (2H, m), 5.26 (2H,s), 6.72 (1H, d), 6.78 (1H, d), 7.59 (2H, d), 7.77 (2H, d), 7.87 (1H,s), 8.41 (1H, s), 9.79 (1H, s), 10.48 (1H, s); m/z (ES+), [M+H]+=492;acid, HPLC tR=1.44 min.

The intermediates used in Example 20 were prepared as follows:

Preparation of 5-Methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one

Potassium tert-butoxide (4.3 g, 38.6 mmol) was added to7-fluoro-5-methoxyquinazolin-4(3H)-one (3 g, 15.5 mmol) and2-methoxyethan-1-ol (1.76 g, 23.2 mmol) in DMSO (30 mL) under nitrogen.The resulting solution was stirred at 80° C. for 15 hours. The reactionmixture was neutralised with 2M HCl. The combined aqueous layer wasdried by lyophilization. The reaction mixture was diluted with DCM (30mL) and TBME (70 mL). The resulting precipitate was collected byfiltration, washed with DCM (10 mL) and dried under vacuum to afford thetitle compound as a white solid (2.2 g, 57%), which was used withoutfurther purification. 1H NMR (400 MHz, DMSO-d6) 3.66-3.77 (2H, m), 3.88(3H, s), 4.19-4.32 (2H, m), 6.71 (1H, d), 6.81 (1H, d), 8.74 (1H, s);m/z (ES+), [M+H]+=251; base, HPLC tR=0.46 min.

Preparation ofN1-(5-Methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)benzene-1,4-diaminehydrochloride

PyAOP (5.5 g, 10.6 mmol) was added to5-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one (2.2 g, 8.8 mmol) andDBU (2.7 mL, 17.6 mmol) in acetonitrile (100 mL) at 25° C. undernitrogen. The resulting solution was stirred at room temperature for 5minutes. Benzene-1,4-diamine (1.5 g, 14.1 mmol) was added to this at 25°C. under nitrogen. The resulting solution was stirred at roomtemperature for 3 hours. The reaction mixture was concentrated anddiluted with DCM (500 mL), and washed sequentially with saturated NaHCO₃(100 mL) and saturated aqueous NH₄Cl (100 mL). The organic layer wasdried, filtered and evaporated to afford crude product. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 4% methanol in DCM. Pure fractions were evaporated to dryness toafford crude product as a pale yellow oil. The reaction mixture wasdiluted with HCl (4 M in dioxane, 2 mL) and acetone (10 mL). Theprecipitate was collected by filtration, washed with acetone (10 mL) anddried under vacuum to afford the title compound as a brown solid. Thesolid was dissolved in DCM (300 mL), and washed sequentially withsaturated NaHCO₃ (50 mL). The organic layer was dried, filtered andevaporated to afford the title compound as a yellow solid (1.2 g, 40%).1H NMR (400 MHz, DMSO-d6) δ 3.33 (3H, s), 3.67-3.74 (2H, m), 4.05 (3H,s), 4.20-4.26 (2H, m), 4.98 (2H, s), 6.58 (2H, d), 6.65 (1H, d), 6.72(1H, d), 7.33 (2H, d), 8.28 (1H, s), 9.47 (1H, s); m/z (ES+),[M+H]+=341; base, HPLC tR=0.7 min.

Example 21N-{4-[(5-Fluoro-7-methoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide

HATU (0.3 g, 0.8 mmol) was added to a solution ofN1-(5-fluoro-7-methoxyquinazolin-4-yl)benzene-1,4-diamine (0.2 g, 0.7mmol) and DIPEA (0.5 mL, 2.7 mmol) in DMF (5 mL). The mixture wasstirred at ambient temperature for 6 hours. The reaction mixture waspoured into water (40 mL) and stirred for 5 minutes. Ethyl acetate (30mL) was added and the organic layer separated. The aqueous layer wasextracted with ethyl acetate (30 mL) and the extracts combined andwashed with saturated brine (2×30 mL) and evaporated to dryness. Theresidue was purified by flash silica chromatography, eluting with agradient of 0-10% (10:1 ethyl acetate:methanol with 1% NH₃) in ethylacetate. Appropriate fractions were evaporated to dryness to afford thetitle compound as a white solid (70 mg, 25%). 1H NMR (500 MHz. DMSO, 27°C.) δ 1.24 (3H, s), 1.25 (3H, s), 2.99 (1H, hept), 3.92 (3H, s), 5.26(2H, s), 7.04 (1H, d), 7.11 (1H, dd), 7.55-7.62 (2H, m), 7.63-7.7 (2H,m), 7.86 (1H, d), 8.45 (1H, s), 8.95 (1H, d), 10.48 (1H, s); m/z: ES+[M+H]+ 436.

The intermediates used in Example 21 were prepared as follows:

Preparation of 2-Amino-6-fluoro-4-methoxybenzonitrile

Ammonium hydroxide (5.2 mL, 41.4 mmol) was added to a microwave vialcontaining 2,6-difluoro-4-methoxybenzonitrile (1 g, 5.9 mmol) inisopropanol (1 mL). The resulting solution was sealed and stirred at 80°C. for 16 hours. The reaction mixture was concentrated and ethyl acetate(75 mL) was added. The organic layer were isolated and washed withsaturated brine (10 mL) then evaporated to afford the title compound(0.8 g, 86%) which was used without further purification. 1H NMR (500MHz, DMSO, 27° C.) δ 3.72 (3H, s), 6.11 (1H, dd), 6.15 (1H, dd), 6.36(2H, s); m/z: ES− [M−H]− 165.

Preparation of(E)-N′-(2-Cyano-3-fluoro-5-methoxyphenyl)-N,N-dimethylformimidamide

1,1-Dimethoxy-N,N-dimethylmethanamine (6.9 ml, 51.8 mmol) was added to2-amino-6-fluoro-4-methoxybenzonitrile (0.9 g, 5.2 mmol) at 25° C. Theresulting slurry was stirred at 80° C. for 2 hours and then cooled toroom temperature. Water (10 mL) was added and the reaction mixturestirred for 1 hour. A precipitate formed which was collected byfiltration to give the title compound as a pink solid (0.8 g, 72%) whichwas used without further purification. 1H NMR (500 MHz, DMSO, 27° C.) δ2.98 (3H, s), 3.07 (3H, s), 3.81 (3H, s), 6.53-6.59 (2H, m), 8.01 (1H,s); m/z: ES+ [M+H]+ 222.

Preparation of 5-Fluoro-7-methoxy-N-(4-nitrophenyl)quinazolin-4-amine

4-Nitroaniline (259 mg, 1.9 mmol) was added to(E)-N′-(2-cyano-3-fluoro-5-methoxyphenyl)-N,N-dimethylformimidamide (277mg, 1.3 mmol) in acetic acid (7 mL). The resulting solution was stirredat 120° C. for 2 hours. Upon cooling the reaction mixture solidified.Ether (15 mL) was added and the solid slurried for 10 minutes. Theresulting yellow solid was collected by filtration, washed withadditional ether and dried under vacuum to give the title compound as atan solid (210 mg, 53%) which was used without further purification. 1HNMR (500 MHz, DMSO, 27° C.) δ 3.95 (3H, s), 7.14 (1H, d), 7.22 (1H, dd),8.08 (2H, d), 8.21-8.29 (2H, m), 8.66 (1H, s), 9.52 (1H, s); m/z: ES+[M+H]+ 315.

Preparation ofN4-(5-Fluoro-7-methoxy-quinazolin-4-yl)benzene-1,4-diamine

5-Fluoro-7-methoxy-N-(4-nitrophenyl)quinazolin-4-amine (0.2 g, 0.7 mmol)in DMF (8 mL) was added to 10% palladium on carbon (0.07 g, 0.1 mmol)under nitrogen. The reaction mixture was allowed to stir for 24 hoursunder hydrogen. The reaction mixture was filtered through celite, washedwith ethyl acetate (30 mL) and the resulting liquors concentrated togive the title compound as a yellow gum (190 mg, 100%). 1H NMR (500 MHz,DMSO, 27° C.) δ 3.90 (3H, s), 5.01 (2H, s), 6.53-6.60 (2H, m), 6.99 (1H,d), 7.05 (1H, dd), 7.20-7.27 (2H, m), 8.34 (1H, s), 8.67 (1H, d); m/z:ES+ [M+H]+ 285.

Example 22N-{4-[(5,7-Dimethoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide

HATU (15.6 g, 40.9 mmol) was added to a mixture ofN1-(5,7-dimethoxyquinazolin-4-yl)benzene-1,4-diamine (8.1 g, 27.3 mmol),2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetic acid (11.9 g, 34.1 mmol) andDIPEA (14.3 mL, 81.9 mmol) in DMF (250 mL). The mixture was stirred atambient temperature for 16 hours. The mixture was quenched by theaddition of water (20 mL). The resulting solution was concentrated to100 mL volume and added to a rapidly stirred mixture of ethyl acetate(250 mL) and water (1300 mL). The mixture was stirred for 1 hour. Theresulting precipitate was collected by filtration and washed with water(400 mL) to give a beige solid. The solid was treated with with 0.1MNaHCO₃ solution (400 mL) and the resulting suspension was sonicated andstirred for 1 hour. The precipitate was collected by filtration andwashed with water. The solid was treated with water (400 mL) and theresulting suspension was sonicated and stirred for 30 minutes. Theprecipitate was collected by filtration, washed with water and dried togive a beige solid (11.2 g). The solid was recrystallised fromacetonitrile (300 mL) to afford the title compound as an off-whitesemi-crystalline solid (8.8 g, 72%). 1H NMR (500 MHz, DMSO, 27° C.) δ1.24 (6H, d), 2.99 (1H, hept), 3.89 (3H, s), 4.07 (3H, s), 5.25 (2H, s),6.68 (1H, d), 6.77 (1H, d), 7.58 (2H, d), 7.76 (2H, d), 7.86 (1H, d),8.40 (1H, s), 9.76 (1H, s), 10.45 (1H, s); m/z: ES+ [M+H]+ 448.

The intermediates used in Example 22 were prepared as follows:

Preparation of N1-(5,7-Dimethoxyquinazolin-4-yl)benzene-1,4-diamine

DBU (18.8 mL, 126 mmol) was added to a mixture of5,7-dimethoxyquinazolin-4(3H)-one (10 g, 48.5 mmol) and PyBOP (32.8 g,63 mmol) in acetonitrile (500 mL). A colourless solution formed that washeated at 60° C. for 1 hour. Benzene-1,4-diamine (10.5 g, 96.9 mmol) wasadded, and stirring at 60° C. continued for a further 2 hours. Themixture was evaporated and the residue was partitioned between DCM (700mL) and saturated ammonium chloride solution (600 mL). The organic layerwas washed with saturated ammonium chloride solution (300 mL), water(600 mL), saturated NaHCO₃ solution (600 mL) and brine (300 mL), driedand evaporated to dryness. The residue was purified by flash silicachromatography, elution gradient 0 to 6% (10:1 methanol/conc. NH₃ (aq))in ethyl acetate. Fractions were evaporated to give the crude product(26 g) as brown semi-solid. This solid was dissolved in acetone (400 mL)and HCl in diethyl ether (2M, 25 mL) was added. The resulting solid wascollected by filtration and washed with acetone to give the crudeproduct, which was partitioned between saturated NaHCO₃ solution (300mL) and DCM (300 mL). The aqueous layer was extracted with DCM (200 mL)and the extracts combined with the organic layer. The combined organicextracts were filtered through a phase-separating paper and evaporatedto dryness. The residue was triturated with diethyl ether to afford thetitle compound as an orange solid (8 g, 55%). 1H NMR (500 MHz, DMSO, 27°C.) δ 3.87 (3H, s), 4.03 (3H, s), 4.97 (2H, s), 6.57 (2H, d), 6.63 (1H,d), 6.71 (1H, d), 7.31 (2H, d), 8.28 (1H, s), 9.45 (1H, s); m/z: ES+[M+H]+ 297.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom hydrogen and fluoro; R² is selected from fluoro and C₁₋₂ alkoxy; R³is selected from hydrogen and methoxy; and R⁴ is a C₁₋₃ alkyl,optionally substituted with a group selected from C₁₋₃ alkoxy and NR⁵R⁶,wherein R⁵ and R⁶ are each independently hydrogen or methyl; or a 4 to 6membered heterocyclyl ring containing one oxygen atom.
 2. The compoundof Formula (I), or a pharmaceutically acceptable salt thereof, asclaimed in claim 1, wherein R¹ hydrogen.
 3. The compound of Formula (I),or a pharmaceutically acceptable salt thereof, as claimed in claim 1,wherein R² is fluoro.
 4. The compound of Formula (I), or apharmaceutically acceptable salt thereof, as claimed in claim 1, whereinR³ is hydrogen.
 5. The compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, as claimed in claim 1, wherein R⁴ is selectedfrom methyl, ethyl, isopropyl, oxetanyl, tetrahydrofuranyl, oxanyl,2-dimethylaminoethyl and 2-methoxyethyl.
 6. The compound of Formula (I),or a pharmaceutically acceptable salt thereof, as claimed in claim 5,wherein R⁴ is 2-methoxyethyl.
 7. The compound of Formula (I), or apharmaceutically acceptable salt thereof, as claimed in claim 1, whereinthe compound is selected from the group consisting of:N-{4-[(5,7-Dimethoxyquinazolin-4-yl)amino]-3-fluorophenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;N-{4-[(5-Fluoro-6,7-dimethoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;(R)—N-(4-{[5-Ethoxy-7-(tetrahydrofuran-3-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;(S)—N-(4-{[5-Ethoxy-7-(tetrahydrofuran-3-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;N-(4-((5-Ethoxy-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide;N-(4-((7-(2-(Dimethylamino)ethoxy)-5-ethoxyquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide;N-(4-((5-Ethoxy-7-methoxyquinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide;N-(4-((5-Ethoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide;N-(4-((5-Ethoxy-7-(oxetan-3-yloxy)quinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide;N-(4-{[5-Methoxy-7-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;2-[4-(Propan-2-yl)-1H-1,2,3-triazol-1-yl]-N-{4-[(5,6,7-trimethoxyquinazolin-4-yl)amino]phenyl}acetamide;N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;(R)-2-(4-Isopropyl-1H-1,2,3-triazol-1-yl)-N-(4-((5-methoxy-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)phenyl)acetamide;(S)-2-(4-Isopropyl-1H-1,2,3-triazol-1-yl)-N-(4-((5-methoxy-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)phenyl)acetamide;N-(4-{[5-Methoxy-7-(propan-2-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;N-(4-{[5-Methoxy-7-(oxetan-3-yloxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;N-[4-({7-[2-(Dimethylamino)ethoxy]-5-methoxyquinazolin-4-yl}amino)phenyl]-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;N-{4-[(7-Ethoxy-5-methoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;N-{4-[(5,7-Diethoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;N-(4-{[5-Methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;N-{4-[(5-Fluoro-7-methoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide;andN-{4-[(5,7-Dimethoxyquinazolin-4-yl)amino]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide.8.-15. (canceled)
 16. A pharmaceutical composition which comprises acompound of Formula (I), or a pharmaceutically acceptable salt thereof,as claimed in claim 1, and at least one pharmaceutically acceptablediluent or carrier. 17.-19. (canceled)
 20. A method for treating cancerin a warm-blooded animal in need of such treatment, which comprisesadministering to the warm-blooded animal a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, as claimed in claim
 1. 21.N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide.22. A pharmaceutically acceptable salt ofN-(4-{[5-Fluoro-7-(2-methoxy-ethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide.23. The pharmaceutically acceptable salt, as claimed in claim 22,wherein the salt is a tosylate salt ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]-amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide.24. A pharmaceutical composition which comprisesN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]-acetamide,or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable diluent or carrier.
 25. The pharmaceuticalcomposition, as claimed in claim 24, wherein the composition comprisesN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}-phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide.26. The pharmaceutical composition, as claimed in claim 24, wherein thecomposition comprises a pharmaceutically acceptable salt ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]-acetamide.27. The pharmaceutical composition, as claimed in claim 24, wherein thecomposition comprises a pharmaceutically acceptable tosylate salt ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]-acetamide.28. The pharmaceutical composition, as claimed in claim 24, wherein thecomposition is an oral pharmaceutical composition.
 29. A method fortreating cancer in a human in need of such treatment, which comprisesadministering to the human a therapeutically effective amount ofN-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide,or a pharmaceutically acceptable salt thereof, and wherein the cancer isselected from the group consisting of gastrointestinal stromal tumour,melanoma, lung cancers, glioblastoma, leukemias, testicular carcinomas,and head and neck cancers.
 30. The method of treating, as claimed inclaim 29, wherein the cancer is gastrointestinal stromal tumour.
 31. Themethod of treating, as claimed in claim 29, wherein the cancer isglioblastoma.
 32. The method of treating, as claimed in claim 29,wherein the cancer is lung cancer.
 33. The method of treating, asclaimed in claim 32, wherein the lung cancer is squamous carcinoma ofthe lung.
 34. The method of treating, as claimed in claim 29, whereinthe cancer is leukemia.
 35. The method of treating, as claimed in claim29, wherein the leukemia is acute myeloid leukaemia or mast cellleukemia.